Asymmetric membranes in delivery devices

ABSTRACT

A device for controlled release of an active substance through one or more asymmetric membranes by diffusion and/or osmotic pumping.

This application is a divisional of U.S. application Ser. No. 07/951,931filed on Sep. 25, 1992 now U.S. Pat. No. 5,612,059 which is acontinuation of application Ser. No. 07/391,741 filed on Aug. 9, 1989,now abandoned, which was a continuation-in-part of application Ser. No.07/238,371 filed on Aug. 30, 1988, now abandoned. The priority of allsuch applications is hereby claimed.

BACKGROUND OF THE INVENTION

Asymmetric membranes, which consist of a very thin, dense skin supportedby a thicker, porous sub-structure layer, are used extensively in thereverse-osmosis desalination of brine. The technology for the formationof economically feasible asymmetric membranes for reverse osmosis wasdeveloped by Loeb and Sourirajan Adv. Chem. Ser. 38, 117 (1962)! andcontinues to be improved.

Asymmetric membranes of polyquinoxalines have been employed in theseparation of gaseous mixtures (U.S. Pat. No. 4,732,586).

While the literature is replete with descriptions of tablets, capsulesand multiparticulates which deliver active substances by diffusion orosmotic pumping, none have taught the use of delivering activesubstances using a device with a coating comprised of an asymmetricmembrane.

SUMMARY OF THE INVENTION

It has now been found that a device for controlled release of one ormore active substances into an environment of use, said devicecomprising a core of said substances, with or without one or moreexcipients, surrounded by one or more asymmetric membranes is feasibleand practical.

A preferred feature of the device is a membrane which is permeable andimperforate and where the release is either substantially by osmoticpumping or substantially by diffusion.

A second preferred feature of the device is a membrane which ispermeable and perforate and where the release is either substantiallyosmotic pumping or substantially by diffusion.

A third preferred feature is a device in which the asymmetric membraneis a cellulose ester or ethyl cellulose.

A fourth preferred feature is a device in the form of a tablet, capsuleor bead.

A fifth preferred feature is a device having a membrane which issemipermeable and imperforate, where the release is substantiallyosmotic pumping and the device is in the form of a capsule, tablet orbead.

The present invention also includes a tablet, capsule or bead foradministration to an animal which releases one or more pharmaceuticallyactive substances into said animal over an appreciable time intervalwhich comprises a core of said active substance or substances, with orwithout one or more pharmaceutically acceptable excipients, said corebeing surrounded by one or more asymmetric membranes.

A preferred feature is a tablet, capsule or bead, wherein theadministration is oral and the release is into the fluid of thegastrointestinal tract of said animal.

Preferred is a tablet, capsule or bead wherein the active substance isan antihypertensive agent. Especially preferred are prazosin,nifedipine, trimazosin and doxazosin.

Also preferred is a tablet, capsule or bead wherein the active substanceis an antianxiety agent. Especially preferred are hydroxyzine andsertraline.

Also preferred is a tablet, capsule or bead wherein the active substanceis an anticlotting agent. Especially preferred is dazmergrel.

Also preferred is a tablet, capsule or bead wherein the active substanceis a hypoglycemic agent. Especially preferred is glipizide.

Also preferred is a tablet, capsule or bead wherein the active substanceis a decongestant, an antihistamine or cough or cold agent. Especiallypreferred are brompheniramine, dexbrompheniramine and chlorpheniraminemaleates, phenylephrine and pseudoephedrine hydrochlorides andcetirizine.

The present invention also includes a process for preparing a tablet forcontrolled release of one or more active substances into an environmentof use, said tablet comprised of a core of said active substances, withor without one or more excipients, surrounded by an asymmetric membranewherein said membrane is formed by a phase inversion process.

Preferred is a wet process which comprises the steps of:

a) coating said core with a solution comprised of about 10-20% of acellulose ester or ethyl cellulose by weight and, optionally, about0-35% of one or more pore-forming substances by weight in acetone,

b) immersing the coated core into an aqueous quench bath and

c) drying.

Preferred in this process is the use of cellulose acetate 398-10 presentin the amount of 15% by weight and the pore-forming substances areformamide, acetic acid, glycerol, a (C₁ -C₄)alkanol, sodium acetate,aqueous hydrogen peroxide or polyvinylpyrrolidone. Especially preferredis the use of ethanol as a pore-forming agent, present in the amount of30% by weight or the use of glycerol as a pore-forming agent, present inthe amount of 10% by weight.

A second preferred wet process for preparing tablets comprises the stepsof:

a) coating said core with a solution comprised of abut 10-20% of acellulose ester or ethyl cellulose by weight and, optionally, about0-40% of one or more pore-forming substances by weight in acetone,

b) immersing the coated core into water until the membrane hassolidified,

c) immersing the coated core into isopropanol until the water has beenreplaced by isopropanol,

d) immersing the coated core in hexane until the isopropanol has beenreplaced by hexane and drying.

Preferred in this process is the use of cellulose acetate 398-10 presentin the amount of 15% by weight and the pore-forming substances areformamide, acetic acid, glycerol, a (C₁ -C₄)alkanol, sodium acetate,aqueous hydrogen peroxide or polyvinylpyrrolidone. Especially preferredis the use of ethanol, as a pore-forming agent, present in the amount of30% by weight.

Another preferred phase inversion process for preparing tablets is a dryprocess comprising the steps of:

a) coating said core with a solution comprised of 10-20% of a celluloseester or ethyl cellulose by weight and about 20-40% of one or morepore-forming substances by weight in acetone and

b) drying the tablet.

Preferred in this process is the use of cellulose acetate 398-10 presentin the amount of 15% by weight and the pore-forming substances arecomprised of glycerol, water, butanol and ethanol present in the amountof 1.9, 2.7, 11.7 and 21.7%, respectively, by weight.

Also part of the present invention is a process for preparing a capsulefor controlled release of one or more active substances into anenvironment of use, said capsule comprised of a core of said activesubstances, with or without one or more excipients, surrounded by anasymmetric membrane, wherein said membrane is formed by a phaseinversion process.

Preferred is a wet process which comprises the steps of:

a) coating a mandrel device, sized and shaped to match the innerdimensions of the desired capsule, with a solution comprised of about10-20% of a cellulose ester or ethyl cellulose by weight and,optionally, about 0-40% of one or more pore-forming substances by weightin acetone,

b) immersing the coated device into an aqueous quench bath,

c) drying,

d) removing the capsule shell from the device,

e) filling the capsule shell with the core material and

f) sealing the capsule.

Preferred in this process is the use of cellulose acetate 398-10 presentin the amount of 16% by weight and the pore-forming substance isformamide, acetic acid, glycerol, a (C₁ -C₄)alkanol, sodium acetate,aqueous hydrogen peroxide or polyvinylpyrrolidone. Especially preferredis the use of ethanol and glycerol as pore-forming substances, presentin the amount of 28 and 8%, respectively, by weight. Also especiallypreferred is the use of glycerol as the pore-forming substance, presentin the amount of 10% by weight.

Also part of the present invention is a process for preparing beads forcontrolled release of one or more active substances into an environmentof use, said beads comprised of a core of said active substances, withor without one or more excipients, surrounded by an asymmetric membranewherein said membrane is formed by a phase inversion process.

Preferred is a dry process comprising the steps of:

a) spray drying a slurry of said active substances in the form of beadscoated with a solution comprised of about 10-20% of a cellulose ester orethyl cellulose by weight and about 20-40% of one or more pore-formingsubstances by weight in acetone into a chamber maintained at about25°-95° C., and

b) separating the dried beads from any excess polymer by sieving or byusing cyclones.

Preferred within this process is the use of a pore-forming mixturecomprising 38% by weight of the total and composed of ethanol, butanol,water and glycerol present in the amount of 57, 31, 7 and 5%,respectively, by weight, and the cellulose ester is cellulose acetate398-10 present in the amount of 15% by weight. Especially preferred isthe spray drying under a pressure of 10-100 psi above atmosphericpressure into a chamber at atmospheric pressure.

Also preferred within this process for preparing beads is a wet processwhich comprises the steps of:

a) coating said core of active substances in the form of beads with asolution comprised of about 10-20% of a cellulose ester or ethylcellulose by weight and, optionally, about 0-40% of one or morepore-forming substances by weight in acetone,

b) immersing the coated beads into an aqueous quench bath,

c) removing the beads after the membrane has solidified and drying.

Preferred in this process is the use of cellulose acetate 398-10 presentin the amount of 15% and the pore-forming substance is ethanol presentin the amount of 33% by weight.

The present invention also relates to a method for releasing one or moreactive substances into an environment of use which comprises placing insaid environment a device containing said active substances surroundedby an asymmetric membrane.

Preferred in this method is a device which is a tablet, capsule or bead.Especially preferred is said device wherein the membrane is permeableand imperforate or perforate, and the release is substantially either bydiffusion or osmotic pumping. Also especially preferred is said devicewherein the membrane is semipermeable and imperforate and the release issubstantially osmotic pumping.

The present invention also relates to a capsule device for thecontrolled release of one or more active substances into an environmentof use, said device comprising a core of said substances, with orwithout excipients, enclosed in a capsule the top or bottom of which iscomprised of one or more asymmetric membranes. Preferred is said devicewherein the membrane is permeable and perforate or imperforate.Especially preferred is such a device wherein the release is by osmoticpumping.

Finally, the instant invention relates to a process for preparing acapsule shell to be used for controlled release of one or more activesubstances into an environment of use, said shell comprised of anasymmetric membrane, wherein said membrane is formed by a phaseinversion process.

Preferred is a wet process which comprises the steps of:

a) coating a mandrel device, sized and shaped to match the innerdimensions of the desired capsule, with a solution comprised of about10-20% of a cellulose ester or ethyl cellulose by weight and,optionally, about 0-40% of one or more pore-forming substances by weightin acetone,

b) immersing the coated device into an aqueous quench bath,

c) drying and

d) removing the capsule shell from the device.

Preferred in this process is the use of cellulose acetate 398-10 presentin the amount of 16% by weight and the pore-forming substance isformamide, acetic acid, glycerol, a (C₁ -C₄)alkanol, sodium acetate,aqueous hydrogen peroxide or polyvinylpyrrolidone. Especially preferredis the use of ethanol and glycerol as pore-forming substances, presentin the amount of 28 and 8%, respectively, by weight. Also especiallypreferred is the use of glycerol as the pore-forming substance, presentin the amount of 10% by weight.

The present invention also relates to a process for preparing a bead,tablet or capsule device for controlled release of one or more activesubstances into an environment of use, said device comprised of a coreof said active substances, with or without excipients, surrounded bymore than one asymmetric membrane wherein said membranes are formed by aphase inversion process.

Preferred is a dry process comprising spray coating of said devicesuspended in the temperature controlled air flow of a fluidized bedcoating system with a solution comprised of about 5-10% of a celluloseester or ethyl cellulose by weight and about 35-40% of one or morepore-forming substances by weight in acetone until the desired number ofasymmetric membranes have been applied. Especially preferred is the useof ethanol as the pore-former and cellulose acetate 398-10 as themembrane material.

The present invention also includes a process for preparing a tablet forcontrolled release of one or more active substances into an environmentof use, said tablet comprised of a core of said active substances, withor without one or more excipients, surrounded by an asymmetric membranewherein said membrane is formed by a phase inversion process.

Preferred is a dry process comprising spray coating said core in aperforated pan coating machine with a solution comprised of about 10-15%of a cellulose ester or ethyl cellulose by weight and about 20-40% ofone or more pore-forming substances by weight in acetone. Especiallypreferred is the use of cellulose acetate 398-10 and glycerol, water,butanol and ethanol together as pore-formers in the amount of 2, 2.8,12.4 and 22% by weight, respectively.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the SEM (scanning electron microscope) cross section of anasymmetric membrane tablet coating having a dense imperforate skin priorto use. The membrane was prepared according to the procedure of Example1, employing a phase inversion-wet process and using cellulose acetateas the membrane material and formamide as the pore-forming substance.

FIG. 2 shows the SEM cross section of an asymmetric membrane tabletcoating having an imperforate dense skin. The tablet membrane wasprepared according to the procedure of Example 2, utilizing a phaseinversion wet process wherein the coated tablet was immersed in anaqueous quench bath.

FIG. 3 shows SEM of an imperforate asymmetric membrane coated tabletprepared by the procedure of Example 3, using a phase inversion dryprocess.

FIG. 4 shows the release rate of the antihypertensive agent, trimazosin,from an asymmetric-membrane-coated tablet, as prepared in Example 1, anda similar tablet coated with a dense membrane with a hole drilledthrough the membrane.

FIG. 5 shows the osmotic release rate of the antihypertensive agent,trimazosin, from an asymmetric membrane coated tablet prepared by theprocedure of Example 1.

FIG. 6 shows the effect of various levels of the pore-forming substanceformamide on the release rate of an asymmetric membrane coated tabletprepared by the procedure of Example 8.

FIG. 7 is a plot showing the change in release rates of theantihypertensive agent doxazosin with changes in the osmotic pressure ofthe core matrix from an asymmetric membrane coated tablet.

FIGS. 8, 9, 10 and 11 are SEM which show the effects of increasingamounts of the pore-forming substance glycerol on the size of holes orports in the dense membrane of an asymmetric membrane coated tablet,prepared in Example 11.

FIG. 12 shows the SEM of dense skin of an asymmetric membrane coatedtablet prepared by a wet phase inversion process, as described inExample 12, where sodium acetate was employed as a pore-formingsubstance.

FIG. 13 shows an SEM cross section of capsule wall formed from anasymmetric membrane prepared by the procedure of Example 15.

FIG. 14 shows the release rate of doxazosin from capsules, made of anasymmetric membrane, into media at varying osmotic pressures.

FIG. 15 depicts SEM of the outer surface and cross section of a capsulemade of an asymmetric membrane in which glycerol was employed as thepore-forming substance.

FIG. 16 shows an SEM of the surface and cross section of a bead coveredwith an asymmetric membrane and made by the procedure described inExample 20.

FIG. 17 shows an SEM of the surface and cross section of a bead triplecoated with an asymmetric membrane layer, prepared as described inExample 21. Note that only one dense skin is visible.

FIG. 18 shows the release rate of doxazosin from asymmetric membranecoated beads having from one to three coats of an asymmetric membrane.

FIG. 19 depicts the release rate of doxazosin from triple asymmetricmembrane coated beads into solutions of different osmotic pressures.

FIG. 20 shows an SEM of the surface, with macro-pores, of a beadsurrounded with an asymmetric membrane prepared by a phase inversion dryprocess as described in Example 23.

FIG. 21 shows the release of trimazosin from beads covered with anasymmetric membrane into water and into a magnesium sulfate solution.The membrane was prepared according to a phase inversion wet process asdescribed in Example 24.

FIG. 22 shows an SEM of the cross section of a capsule wall made of aasymmetric membrane comprised of ethylcellulose and prepared in Example27.

FIG. 23 shows the SEM of a cross section capsule wall made of acellulose acetate butyrate asymmetric membrane as prepared in Example28.

FIG. 24 shows the SEM of a cross section of a capsule wall made of ablend ethylcellulose and cellulose acetate asymmetric membrane (Example29).

FIG. 25 shows the SEM of a cross section of a capsule wall made of ablend cellulose acetate butyrate and ethylcellulose asymmetric membrane(Example 30).

FIG. 26 shows the SEM of a cross section of an asymmetric membranecapsule wall made of a blend of cellulose acetate butyrate and celluloseacetate (Example 31).

FIG. 27 shows the SEM of a cross section of an asymmetric membranecapsule wall made of cellulose acetate propionate, prepared according toExample 32.

FIG. 28 shows the SEM of a cross section of an asymmetric membranecapsule wall made of nitro-cellulose, prepared by the procedure ofExample 33.

FIG. 29 shows the SEM of a cross section of an asymmetric membranecapsule wall made of cellulose acetate phthalate, prepared according toExample 34.

FIG. 30 shows the SEM of a cross section of an asymmetric membranecapsule wall made of cellulose acetate trimellitate, prepared by theprocedure of Example 35.

FIG. 31 shows the SEM of a cross section of an asymmetric membranecapsule wall made of polyvinyl alcohol by the procedure of Example 36.

FIG. 32 shows the SEM of a cross section of an asymmetric membranecapsule wall made of ethylenevinyl alcohol, prepared according toExample 37.

FIG. 33 shows an SEM of a cross section of an asymmetric membranecapsule wall made of polyurethane by the prcedure of Example 38.

FIG. 34 shows the SEM of a cross section of an asymmetric membranecapsule wall made of polyvinylidene fluoride, prepared by the procedureof Example 39.

FIG. 35 shows the SEM of a cross section of an asymmetric membranecapsule wall made of polysulfone, prepared according to Example 40.

FIG. 36 shows the SEM of the cross section of an asymmetric membranecapsule wall made of polymethyl methacrylate by the procedure of Example41.

FIG. 37 shows the SEM of a cross section of an asymmetric membranecapsule wall made of polyamide by the procedure of Example 42.

FIG. 38 shows the SEM of a cross section of an asymmetric membranecapsule wall made of a blend of ethylcellulose and cellulose acetatephthalate by the procedure of Example 43.

FIG. 39 shows the SEM of a cross section of an asymmetric membranecapsule wall made of a blend of ethylcellulose and cellulose acetatetrimellitate by the procedure of Example 44.

FIG. 40 shows the SEM of a cross section of an asymmetric membrane wallmade of ethylcellulose on a drug containing bead, prepared by theprocedure of Example 45.

FIG. 41 shows the SEM of a cross section of an asymmetric membrane wallmade of cellulose acetate butyrate on a drug containing bead, andprepared according to Example 46.

FIG. 42 shows water fluxes and corresponding release rates from variousasymmetric membrane capsules prepared according to Example 47.

FIG. 43 shows the SEM of the cross section of multiple layers ofasymmetric membranes made of cellulose acetate on beads according toExample 49.

FIG. 44 shows release rate of an active substance from capsules made ofan asymmetric membrane using different ratios of plasticizers as inExample 52.

DETAILED DESCRIPTION OF THE INVENTION

As previously indicated, an asymmetric membrane is comprised of tworegions or membrane layers. The substructure is relatively thick andvery porous in nature. This substructure supports the other portion ofthe membrane, a very dense, thin skin.

The materials of which the asymmetric membranes of the present inventionare made consist of cellulose derivatives. In particular, they consistof cellulose esters and ethers, namely, the mono-, di- and triacylesters wherein the acyl group consists of two to four carbon atoms andlower alkyl ethers of cellulose wherein the alkyl group is of one tofour carbon atoms. The cellulose esters can also be mixed esters, suchas cellulose acetate butyrate, or a blend of cellulose esters. The samevariations can be found in ethers of cellulose and includes blends ofcellulose esters and cellulose ethers. Other cellulose derivatives whichcan be used in making the asymmetric membranes of the present inventioninclude those materials which are associated with reverse osmosismembranes, and include cellulose nitrate, acetaldehyde dimethylcellulose, cellulose acetate ethyl carbamate, cellulose acetatephthalate, cellulose acetate methyl carbamate, cellulose acetatesuccinate, cellulose acetate dimethaminoacetate, cellulose acetate ethylcarbonate, cellulose acetate chloroacetate, cellulose acetate ethyloxalate, cellulose acetate methyl sulfonate, cellulose acetate butylsulfonate, cellulose acetate p-toluene sulfonate, cellulosecyanoacetates, cellulose acetate trimellitate and cellulosemethacrylates.

These materials can be formed by the acylation of cellulose with thecorresponding acyl anhydride or acyl halide. Several of the commoncellulose esters are available commercially. cellulose acetate 394-60,398-10 and 400-25, having acetyl contents of 39.4, 39.8 and 40%,respectively, are readily available from Eastman Chemical Co.,Kingsport, Tenn.

In addition to cellulose derivatives, materials useful for fabricatingasymmetric membranes include polysulfones, polyamides, polyurethanes,polypropylene, ethylene-vinyl acetate, polyvinyl chloride, polyvinylalcohol, ethylenevinyl alcohol, polyvinylidene fluoride, polymethylmethacrylate as well as many others.

As mentioned, it has now been found that tablets and multiparticulatesor beads can be coated with an asymmetric membrane and capsule shellscan be made of an asymmetric membrane for release of one or more activesubstances in an environment of use over a period of time.

The process by which this membrane is formed is a phase inversionprocess (R. E. Kesting, "Synthetic Polymeric Membranes,"Wiley-Interscience, 2nd Ed., 1985). In this process a polymer solutionis induced to undergo phase separation in a particular way, resulting ina structured, continuous polymer phase. In preparing the membrane of thepresent invention the process can be a wet process or a dry process. Inthe wet process the polymer is dissolved in a solvent system consistingof one or more solvents. A film of this solution is coated on a deliverydevice, in particular a tablet, bead or capsule form, and following anoptional period of air drying, the coated device is immersed in a quenchbath consisting of a solvent in which the polymer is not soluble, but inwhich the original polymer solvent system is soluble. The quench bathextracts the solvent or solvents from the film of coated polymersolution, resulting in a precipitation of the polymer in the form of astructured membrane on the device. In the wet process several baths canbe used, the polymer being precipitated in the first bath followed byother baths to facilitate drying of the membrane.

The wet process can also use a pore-forming substance or substances toenhance the porous nature of the substructure of the membrane. Thesepore-forming substances are, generally, poor solvents for the polymerand are usually dissolved out in the quench bath at the time the polymeris precipitated.

The dry process also provides an asymmetric membrane and utilizes asolvent system for the polymer and a pore-forming substance, which is anon-solvent for the polymer. As in the wet process the device is coatedwith a solution of polymer and pore-forming substance; however, in thedry process the solvent is allowed to evaporate completely. Thesuccessful formation of an asymmetric membrane using the dry processrequires that the solvent or solvents evaporate more rapidly than thepore-forming substance. In addition, the pore-forming substance must notbe a solvent for the polymer.

As mentioned above, pore-forming substances are employed to control theporosity of the substructure of the asymmetric membrane. The porouschannels in the substructure of the polymer can extend through the denseskin, resulting in macropores or a series of holes on the exterior skinof the device. Thus, by increasing the pore-forming substance it ispossible to progress from a device having a porous substructure and animperforate skin to one having a highly perforate skin (FIGS. 8, 9, 10and 11--Example 11).

Pore-forming substances in the wet process include formamide, aceticacid, glycerol, an alkanol of one to four carbon atoms, 10% aqueoushydrogen peroxide and polyvinylpyrrolidone or combinations thereof.Sodium acetate, or other inorganic salts, can be employed aspore-forming agents as they do not dissolve in the polymer solvents andare dissolved out of the precipitated polymer when the quench is anaqueous quench, leaving macropores in the dense membrane or skin.Suitable pore-forming substances for the dry process include glycerol,water, alkanols, oils, surfactants, glycols or combinations thereof.Rapid drops in pressure during the precipitation of the polymer can alsoresult in enhanced macropore formation when the dry process is employed.For example, spray drying beads coated with a polymer solution underpressure into a chamber at a lower pressure can result in macro-poreformation (FIG. 20--Example 23). When the device of this invention isintended for human or veterinary use, the pore-forming agent should bepharmaceutically acceptable. It should be noted that in the case of somepolymer coating materials little or no pore-forming substances may berequired to give the desired asymmetric membrane.

Asymmetric-membrane coatings with macropores through the outer skin(perforate membrane coatings) can also be made by adjusting thequench-bath conditions. Raising the temperature of the quench bath totemperatures near the boiling point of the solvent used in the polymercoating solution causes rapid evaporation of the solvent and macroporeformation upon precipitation of the polymer in the quench bath. Othernonsolvents, such as ethanol, can be added to the quench bath to causemacropores to form in the membrane coatings. Thus, either perforate orimperforate membranes can be formed depending on the quench-bathtemperature and composition.

Asymmetric-membrane coatings that have macropores through the outer skincan also be made by making membrane coatings using two or moreincompatible polymers. The quantity of macropores through the surfacecan be controlled by the relative concentrations of the incompatiblepolymers. Thus, the structure of the outer surface of the membranecoatings can be made either perforate or imperforate depending on thepolymers used and their concentrations in the coating solution (FIG.24--Example 29).

Macropores can also develop in situ by the rupturing of the dense skinlocated directly over a channel in the substructure. Thus, animperforate membrane becomes perforate during use.

The active substances and excipients are released from the device of thepresent invention by either diffusion or osmotic pumping or acombination of both (FIG. 5--Example 6). Release by diffusion is apassive phenomenon in which the active substance moves from a region ofhigh concentration (the interior of the device) to a region of lowerconcentration (the exterior of the device). Release by osmotic pumpingmakes use of various osmotically effective compounds in the core of thedevice. These osmotically effective compounds are the driving force ofthe device and provide a higher osmotic pressure inside the device thanthat of the exterior environment, which in the case of a medicinal agentbeing given orally to a human, would be aqueous. Such osmoticallyeffective substances include sugars such as sucrose, lactose, fructose,mannitol and the like; water soluble salts, such as sodium chloride,sodium carbonate, potassium chloride, calcium chloride and sodiumsulfate, water soluble acids, alcohols, surfactants and the like. Whenthe device of this invention is intended for human or veterinary use,the osmotic enhancing agents should be pharmaceutically acceptable.

Other excipients present in the devices of this invention include suchwater soluble binders as polyethylene glycol, gelatin, agar,carboxycellulose, ethylmethylcellulose, polyvinyl alcohol, water solublestarch, polyvinylpyrrolidone and the like; water insoluble bindersinclude cellulose acetate, polyurethane, epoxides and the like.Excipients can include lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc, as well as organic acids and inorganicand organic bases to help solubilize the active substances whenreleased.

The environments of use can vary considerably and include human andanimal bodies, soil, plant surfaces, air, aqueous medium and foods andbeverages.

Concerning the active substances, these can vary widely in nature; theycan be drugs, nutrients, plant growth regulators, fertilizers, biocides,insecticides, pesticides, pheromones, germicides, and such common usesas room deodorizers, pool chlorinators, flavors, fragrances and insectrepellents.

When the active substance is a drug, it can be an antihypertensiveantianxiety, bronchodilator, hypoglycemic, a cough or cold agent,antihistamine, decongestant, neoplastic, anti-ulcer, antiinflammatory,hypnotic, sedative, tranquilizer, anesthetic, muscle relaxant,anticonvulsant, antidepressant, antibiotic, analgesic, antiviral, etc.Further such drugs can be in the form of a solution, dispersion, paste,cream, particle, granule, emulsion, suspension or powder.

The shape of the devices of the present invention can also vary greatly.They can be in the form of a tablet, capsule or bead which can be usedfor the adminstration of a medicinal agent to a human, or in the case ofa capsule, can be sufficiently large enough to be used as a bolus inadministering medicinal agents to ruminants. Further, the tablet can beof sufficient size that it can be used to chlorinate pool water over asustained period of time, or to deliver large quantities of other activesubstances.

In summarizing the nature of the membrane of the present devices and themethods for releasing active substances from the core of said device,the membrane can be permeable, meaning that both solvent and activematerial can pass through the membrane, and imperforate, meaning thereare no visible macropores in the dense thin skin. If the skin issufficiently strong or the osmotic core pressure sufficiently low, therelease from this device may be substantially by diffusion (the term"substantially" implies that most, i.e., over 50% of the release is bythis release mechanism). If the thin skin forms macropores in situ, thedevice would continue to release by diffusion. If the core of the devicecontains osmotically effective compounds or substances, the osmoticpressure could rupture the skin over the channels of the substructureand the release will be substantially by osmotic pumping.

The membrane can also be permeable and perforate. The delivery orrelease without osmotic substances will be substantially by diffusionunless the active substance itself is osmotically active. With osmoticenhancing substances in the core of the device the release can besubstantially osmotic pumping.

The membrane can also be semipermeable, meaning that only the solventcan pass through the membrane, and imperforate. If the pressure withinthe core of the device is sufficiently high, macropores can develop insitu, as mentioned previously, and the release will be substantially byosmotic pumping.

The rate of release of the active substances from the devices of thepresent invention can be controlled by the release mechanism, themembrane permeability, the nature of the excipients, the size of thedevice and the size and number of macropores present in the skin of themembrane. In general, release by osmotic pumping releases the activesubstances faster than diffusion, all other factors being the same.Excipients which aid in solubilizing the active substance enhancerelease from the device. Also large and numerous macropores aid in rapiddiffusional release of the active substances. Another factor which caninfluence the rate of release is the thickness of the membrane and thenumber of coats of membrane on the device. In the case of beads the useof multiple coats of membranes will slow the release of activesubstances (FIG. 18--Example 21). The presence of one or moreplasticizers in the material used in making the asymmetric membrane canaffect the permeability of said membrane and hence the rate of releaseof the active substance. In general, hydrophilic plasticizers, such aglycerine, will increase permeability and release rate while hydropholicplasticizers, such as triethylcitrate will reduce permeability and rateof release (FIG. 44--Example 52).

The process for preparing a tablet device surrounded by an asymmetricmembrane, wherein the phase inversion is a wet process, consists of dipcoating a standard tablet containing the appropriate active substancesand desired inert excipients in a solution consisting of about 10-20% byweight of a cellulose derivative or other polymer material and,optionally, 0-35% by weight of one or more pore-forming substances in asolvent consisting of ethyl acetate, methyl ethyl ketone,dimethylformamide, acetone, dioxane or combinations thereof. Thepore-forming substances, if used, should meet the criteria previouslydiscussed. The coated tablet is then immersed in an aqueous quench bath,removed and the tablet dried. Alternately, the tablet, after beingremoved from the aqueous quench bath can be freed of water by using asubsequent immersion in a water soluble, polymer-nonsolubilizing solventsuch as isopropanol. The tablet can be dried at this point or it can beput in a bath of an even more volatile solvent than isopropanol, such ashexane, pentane or cyclohexane. These baths employed subsequent to thewater bath must be polymer nonsolubilizing. The purpose of bathssubsequent to the aqueous quench is to facilitate drying while retainingthe membrane structure.

The process for the preparation of a tablet device surrounded by anasymmetric membrane, wherein the phase inversion is a dry processcomprises dip coating the said standard tablet with a solutionconsisting of 10-20% by weight of the cellulose derivative or otherpolymer material and 20-40% by weight of one or more pore-formingsubstances in a solvent selected from acetone, methylene chloride ordioxane. The coated tablet is then removed and dried.

As indicated previously, beads can have multiple coats of asymmetricmembranes. This requires a repeat of one of the processes mentionedabove.

The preparation of capsule shells made of an asymmetric membraneconsists of dipping a capsule form into a solution of 10-20% by weightof a cellulose derivative or other polymer material and, optionally,0-40% by weight of one or more pore-forming substances in a solvent suchas acetone or dioxane. The coated capsule forms can be immersed in anaqueous quench bath (phase inversion-wet process) and dried, or they canbe air dried without immersing in an aqueous quench bath. Alternately,as with the tablets the coated capsule forms can go through a series ofbaths as previously described.

The dried capsules are removed from the forms, filled with the desiredcore material and a capsule top put on the filled bottom section andsealed by some appropriate method, such as applying overlapping tapearound the joint of the capsule top and bottom.

As previously indicated, capsules having either the top or bottom madeof an asymmetric membrane and the remaining part of an impermeable orsemipermeable material is also contemplated by this invention.

The preparation of beads or multiparticulates surrounded by anasymmetric membrane can be carried out using a phase inversion dry orwet process. Using the dry process, a slurry of active substances andinert excipients in the form of beads in a solution consisting of 10-20%by weight of a cellulose derivative or other polymer material and 20-40%by weight of a pore-forming substance in acetone, dioxane or methylenechloride is spray dried into a room or chamber maintained at about25°-90° C. The separation of the dry coated beads from polymer flakescan be achieved by sieving or by the use of conventional cyclones.

The spray drying can be carried out by a conventional spinning disc orby spraying a slurry of coated beads from a conventional nozzle into aroom or chamber. The formation of macropores in the asymmetric membranecoated beads is enhanced by the nozzle spray drying at a pressure 10-100psi greater than the pressure in the chamber or room.

Beads coated with an asymmetric membrane can also be prepared by thephase inversion wet process which comprises immersing beads coated witha solution of 10-20% by weight of a cellulose derivative or otherpolymer material and, optionally, 0-40% by weight of one or morepore-forming substances in acetone or dioxane into an aqueous quenchbath followed by removal of the beads and drying.

The coated beads of the present invention can be further packaged as adelivery system. For example, the asymmetric membrane coated beads canbe placed in conventional gelatin capsules or in a capsule composed ofan asymmetric membrane if used in human or veterinary medicine.

It has also been found that the devices of the present invention can bemade with multiple asymmetric membranes (FIG. 43--Example 49) by the dryprocess, which comprises coating beads, capsules or tablets in aWurster-type fluidized bed coating system. The devices to be coated canbe beads, tablets or filled capsules prepared with the appropriateactive substances as previously defined. In the case of capsules, theshell thereof can be made of an asymmetric membrane or a conventionalshell, such as a gelatin shell. The devices to be coated are circulatedin the fluidizer bed coating system mentioned above until the desirednumber of multiple coats of asymmetric membrane have been applied. Airflow velocity, air temperature and nozzle velocity of the coating sprayare obvious parameters which can control the length of time necessary toapply the desired number of asymmetric membrane coats.

In addition to using a fluidized bed coating system to making beads,capsules and tablets having multiple asymmetric membranes, aconventional spray coating technique using a rotating pan coater canalso be used.

The following examples illustrate the invention but are not to beconstrued as limiting the same.

EXAMPLE 1 Formation of Asymmetric Membrane Tablet Coating-Wet Process

A coating solution was made of 15 wt % cellulose acetate 398-10 (EastmanChemical Products, Inc.) and 14 wt % formamide, dissolved in acetone,and the solution stored in a sealed container at room temperature untilused.

Trimazosin tablets made by standard direct-compression techniques andconsisting of 40 wt % trimazosin, 58 wt % Avicel PH102 (FMC Corp.), and2 wt % magnesium stearate (total weight of 280 mg) were dip-coated byimmersing them in the coating solution and withdrawing them slowly(about three seconds to completely withdraw a tablet). The tablets werethen air-dried at room temperature for five seconds and then immersed ina water quench bath for three minutes. Immediately after the tabletswere withdrawn from the water quench bath, they were immersed into anisopropyl alcohol solvent-exchange bath for 3 minutes and subsequentlyinto a hexane solvent-exchange bath, also for 3 minutes. The tabletswere then allowed to completely air-dry for at least 12 hours at roomtemperature.

The coatings formed in the manner described above were asymmetric inappearance, as shown in FIG. 1. The coating consisted of a porous layeradjacent to the tablet, extending through almost the entire coatingthickness; on the outside surface a dense skin was formed that wasimperforate prior to use. The overall thickness of the membrane coatingwas approximately 200 μm, and the thickness of the dense outer skin wasless than 1 μm.

EXAMPLE 2 Formation of Asymmetric Membrane Tablet Coating-Wet Process

A coating solution was made of 15 wt % cellulose acetate 398-10 (EastmanChemical Products, Inc.) and 14 wt % formamide, dissolved in acetone,and the solution stored in a sealed container at room temperature untilused.

Trimazosin tablets were dip-coated and quenched in a water bath asdescribed in Example 1. The tablets were then allowed to completelyair-dry at room temperature for at least 12 hours.

The coatings formed in the manner described were asymmetric inappearance, as shown in FIG. 2. The coating consisted of a porous layeradjacent to the tablet, extending through almost the entire coatingthickness; on the outside surface a dense skin was formed that wasimperforate prior to use. The overall thickness of the membrane coatingswas approximately 200 μm, and the thickness of the dense outer skin wasless than 1 μm.

EXAMPLE 3 Formation of Asymmetric Membrane Tablet Coating-Dry Process

A coating solution was made of 15 wt % cellulose acetate 398-10 (EastmanChemical Products, Inc.), 1.9 wt % glycerol, 2.7 wt % water, 11.7 wt %butanol, and 21.7 wt % ethanol dissolved in acetone, and the solutionstored in a sealed container at room temperature until used.

Trimazosin tablets were dip-coated as described in Example 1. Thecoatings were then dried to completion at room temperature in quiescentair. A cross-section of these coatings is shown in FIG. 3. As describedin Examples 1 and 2, the membrane coating consists mostly of a poroussublayer with a thin, dense outer skin. The overall thickness of themembrane was about 125 μm and the thickness of the outer skin was about1 μm. The outer skin was imperforate prior to use.

EXAMPLE 4 Osmotic Release from Tablets Coated With Asymmetric MembraneCoating and Dense Membrane Coating

Individual trimazosin tablets having a weight of 265 mg and containing64 wt % trimazosin, 21 wt % micro-crystalline cellulose, 13 wt % starch,and 5 wt % lubricant were coated with an asymmetric cellulose acetatemembrane coating similar to the coating described in Example 1 and witha dense cellulose acetate membrane coating.

The coating solution for the asymmetric membrane was made of 15 wt %cellulose acetate 398-10 (Eastman Chemical Products, Inc.), 27 wt %formamide, dissolved in acetone at room temperature. After dip coating,the tablets were air-dried for 30 seconds before they were immersed inthe water quench bath for 3 minutes. As in Example 1, the tablets werethen immersed in an isopropyl alcohol solvent-exchange bath for 3minutes, followed by immersion in a hexane solvent-exchange bath for 3minutes before being allowed to dry to completion at room temperature.The average weight of these coatings was 13.3±2.5 mg. Based onmeasurements of coatings made previously in exactly the same manner, theoverall thickness of the coating on these tablets was assumed to beapproximately 250 μm. A 340-μm diameter hole was mechanically drilledthrough the asymmetric membrane coating to function as a drug-deliveryport.

The coating solution for the dense-membrane coatings was made of 15 wt %cellulose acetate 398-10 dissolved in acetone at room temperature. Thetablets were dip-coated, then allowed to air dry before they weredip-coated a second time to increase the coating thickness. The averageweight of these coatings was 25.0±2.2 mg--almost twice the coatingweight of the asymmetric-membrane coatings. The thickness of these densecoatings, approximately 100 μm (less than half the thickness of theasymmetric-membrane coating), was calculated from the average coatingweight, measured surface area, and the reported density for celluloseacetate 398-10. The dense-membrane coatings had about twice as muchcellulose acetate in the coatings and were much thinner than are theasymmetric-membrane coatings. Because the dense membranes wererelatively thin, more coating material was required to form a durablecoating. A 340-μm diameter hole was mechanically drilled through thedense coating to function as a drug-delivery port.

Release-rate tests were conducted by placing the tablets with theasymmetric- and dense-membrane coatings in water at 37° C. The releaseprofiles for both types of coated tablets are shown in FIG. 4. Bothtypes of coated tablets exhibit steady-state constant release rates, asexpected from osmotic delivery systems. The steady-state release ratefrom the tablets coated with the asymmetric-membrane coatings were about65 times higher than those from the same tablets coated with densemembranes. This demonstrates higher water permeability throughasymmetric membrane coatings and subsequently higher release ratescompared with dense coatings made of the same material. The higherrelease rates possible with the asymmetric coatings are advantageouswhen higher drug release rates are desired.

EXAMPLE 5 Osmotic Tablets with Asymmetric Membrane Coating--With andWithout Hole Drilled Through Coating

Trimazosin tablets containing 40 wt % trimazosin, 58 wt % Avicel PH102(FMC Corp.), and 2 wt % magnesium stearate, with a total weight of 350mg, were coated with asymmetric cellulose acetate membrane coatings inthe same manner as described in Example 1. A 340-μm diameter hole wasmechanically drilled through the coating on some of these tablets. Theouter skin of the coatings was continuous except for the drilled holes.

These tablets were release-rate tested in water at 37° C. Therelease-rate results were essentially the same for tablets with andwithout a hole drilled through the coatings. The average release ratefrom the tablets with a hole drilled through the coatings was 4.4±0.1mg/hr compared with 4.7±0.4 mg from the tablets without a hole drilledthrough the asymmetric-membrane coatings. The time lag before drugdelivery began was less than an hour for all the tablets. Tablets with ahole drilled through the coating had a time lag about half that observedfor the tablets without a hole drilled through the coating. Theseresults indicate that drug was pumped out pores in the asymmetricmembrane coating and that drug-delivery ports do not need to beincorporated into asymmetric coatings in a separate processing step, asis required in commercially available osmotic tablets that utilize densecoatings.

EXAMPLE 6 Osmotic Release From Tablets Coated With Asymmetric Membrane

Tablets containing 40 wt % trimazosin, 58 wt % Avicel PH102, and 2 wt %magnesium stearate (total weight of 350 mg) were coated with anasymmetric cellulose acetate membrane coating as described in Example 1.

Release rates were determined from these coated tablets immersed in a2.4-wt % magnesium sulfate solution and water. The osmotic pressure ofthe magnesium sulfate solution was about 6 atm, whereas the osmoticpressure of a saturated solution of trimazosin and the other tabletexcipients was about 3 atm. Thus, there was no osmotic driving force fortrimazosin delivery from these tablets into the magnesium sulfatesolution. The solubility of trimazosin in the magnesium sulfate solutionis the same as the trimazosin solubility in water, so any difference inrelease rates from the tablets placed in magnesium sulfate solution andwater cannot be attributed to different concentration gradients acrossthe membrane. Initially the tablets were placed in a stirred solution of2.4 wt % magnesium sulfate at 37° C. After approximately 3.5 hours thetablets were removed from the magnesium sulfate solution and placed inwater (which has an osmotic pressure of 0 atm) for approximately 3 hoursand then placed back in fresh 2.4-wt % magnesium sulfate solution.Trimazosin release rates into the two solutions vary by approximately anorder of magnitude, as shown in FIG. 1. As expected, the release ratewas very low into the magnesium sulfate solution, since trimazosin couldonly be released into the magnesium sulfate solution by diffusion; therelease rate was much higher into water due to osmotic pumping of thetrimazosin from the tablet. As soon as the osmotic driving force wasremoved (placing the tablets back in a magnesium sulfate solution) therelease rate dropped, convincingly demonstrating osmotic release fromthese coated tablets. If the release rates had been controlled bydiffusion, then the release rates into water and the magnesium sulfatesolution would have been the same.

EXAMPLE 7 Osmotic Release From Tablets Coated With Asymmetric Membrane

Doxazosin tablets containing 0.5 wt % doxazosin, 10 wt % adipic acid, 10wt % PEG 3350, and 79.5 wt % lactose (total weight of 500 mg) werecoated with asymetric-membrane coatings and released into stirred and"unstirred" gastric buffer, and "unstirred" intestinal buffer (both"unstirred" solutions were stirred for 20 seconds each hour before thesample was taken).

The asymmetric coatings were applied in a manner similar to thatdescribed in Example 2. The coating solution consisted of 15 wt %cellulose acetate 398-10 (Eastman Chemical Products, Inc.) and 33 wt %ethanol dissolved in acetone at room temperature. The tablets weredip-coated, air-dried for five seconds, then immersed in a water quenchbath for four minutes and finally allowed to dry to completion at roomtemperature. All solutions and the entire coating process were conductedat room temperature.

Release-rate tests were conducted in gastric and intestinal buffers at37° C. One release-rate test was conducted with stirred (about 150 rpms)gastric buffer and two other release rate tests were conducted in mostlyunstirred gastric and intestinal buffers. The "unstirred" solutions werenot stirred during the release-rate test except for 20 seconds each hourprior to sampling. The gastric buffer contained sodium chloride,hydrochloric acid, and sodium hydroxide, and had a pH of 1.5 and anosmotic pressure of 7 atm. The intestinal buffer contained potassiumphosphate, mono-basic, and sodium hydroxide, and had a pH of 7.5 and anosmotic pressure of 7 atm. Doxazosin solubility in the gastric bufferwas about 250 ppm and in the intestinal buffer was less than 10 ppm. Therelease rate from the tablets placed in stirred (about 150 rpms) gastricbuffer is 0.17±0.01 mg/hr. The release rate from the tablets placed inthe "unstirred" gastric buffer is 0.17±0.02 mg/hr, and the release ratefrom the tablets placed in the "unstirred" intestinal buffer was0.17±0.01 mg/hr. There was virtually no time lag before drug deliveryfrom any of the tablets and all exhibited constant release rates for theduration of the tests (8 hours). Release from osmotic devices istheoretically supposed to be independent of the drug solubility in thereceptor solution and of the stirring rate as long as boundary layersoutside of the osmotic device do not develop. The same release ratesfrom these doxazosin tablets placed in different receptor solutionsdemonstrate osmotic delivery using asymmetric-membrane coatings.

EXAMPLE 8 Demonstration of Variations of the Permeability of AsymmetricMembranes on Coated Tablets

Trimazosin tablets containing 40 wt % trimazosin, 58 wt % Avicel PH102(FMC Corp.), and 2 wt % magnesium stearate with a total weight of 350 mgwere dip-coated and quenched in a water quench bath, then placed insolvent-exchange baths as described in Example 1. The coating solutionsconsisted of 15 wt % cellulose acetate 398-10 (Eastman ChemicalProducts, Inc.) and 7 to 35 wt % formamide, dissolved in acetone. Theasymmetric membrane coatings made with these solutions were 150 μm to250 μm thick. The thickness of the membrane coatings was proportional tothe quantity of formamide in the coating solution.

Release-rate tests were conducted, comparing relative permeabilities ofthe coatings made with coating solutions with different formamidecontents. The coated tablets were placed in water at 37° C. Steady-staterelease rates with respect to the formamide content in the coatingsolution are shown in FIG. 6. The release rates increase as theformamide content increases up to a maximum at a formamide concentrationof about 20 wt %. At higher formamide concentrations the release ratesare lower and less consistent from tablet to tablet. The point on thegraph corresponding to 27 wt % formamide was actually from 280 mgtrimazosin tablets and was normalized with respect to the surface areaof the 350 mg tablets. The increasing release rates indicate that themembrane coatings are becoming more permeable to water with increasingamounts of formamide and subsequently higher release rates are achieved.The membrane coatings with formamide concentrations higher than 20 wt %are evidently less permeable than some of the coatings made with coatingsolutions containing less formamide. This phenomenon has been reportedin literature describing reverse-osmosis membranes. The ability to varythe membrane permeability and subsequently the release rate by alteringthe coating formulation provides added flexibility when designingosmotic delivery systems.

EXAMPLE 9 Enhancement of Osmotic Release Rate from Asymmetric MembraneCoated Tablets

Two types of trimazosin tablets were dip-coated in the same manner asdescribed in Example 1. One type of trimazosin tablet was the same asdescribed in Example 1 except that the total weight was 350 mg ratherthan 280 mg. The other type of trimazosin tablet contained 40 wt %trimazosin, 40 wt % calcium lactate, 18 wt % Avicel PH102 (FMC Corp.),and 2 wt % magnesium stearate (total weight of 350 mg). The osmoticpressure of a saturated trimazosin solution at 37° C. is about 3 atm,and the osmotic pressure of a saturated trimazosin and lactose solutionat 37° C. is about 15 atm. Trimazosin solubility is about 40% lower in asaturated calcium lactate solution than it is in water.

The tablets were placed in water at 37° C. and release rates weredetermined. The release rates from the trimazosin and thetrimazosin/calcium lactate tablets were 4.2±0.05 mg/hr and 7.6±0.42mg/hr, respectively. As expected, the release rate from thetrimazosin/calcium lactate tablets was higher than that from the tabletsthat contained trimazosin as the only soluble component. Release ratesfrom osmotic delivery systems are theoretically proportional to thedifference in osmotic pressures of the solution inside the tablet andthe receptor solution. The release rate from the trimazosin/calciumlactate tablets was similar to the theoretical release rate determinedfrom the release rate of the tablets containing only trimazosin, thedifference in osmotic pressures between the two tablet materials, thesolubility of the trimazosin in water and saturated calcium lactate, andtheoretical boundary layers developed in the asymmetric-membranecoatings.

EXAMPLE 10 Control of Osmotic Release Rate from Assymmetric MembraneCoated Tablets

Doxazosin tablets made with different soluble fillers were released intogastric buffer (osmotic pressure of 7 atm) to demonstrate that theosmotic release rate can be varied by using fillers with differentosmotic pressures. Four different types of doxazosin tablets were madewith soluble fillers that have different osmotic pressures in solution.

1) Doxazosin/ascorbic acid tablets were made with 1 wt % doxazosin, 85wt % ascorbic acid, 13 wt % Avicel PH102 (FMC Corp.), and 1 wt %magnesium stearate. The osmotic pressure of a saturated solution ofthese tablet excipients was about 54 atm (47 atm osmotic driving forcein gastric buffer), and the doxazosin solubility in a saturated solutionof the tablet excipients was about 26 mg/ml.

2) Doxazosin/succinic acid/lactose tablets were made with 1 wt %doxazosin, 49.5 wt % succinic acid, and 49.5 wt % lactose. The osmoticpressure of a saturated solution of these tablet excipients was about 47atm (40 atm osmotic driving force in gastric buffer), and the doxazosinsolubility in a saturated solution of the tablet excipients was about 27mg/ml.

3) Doxazosin/succinic acid tablets were made with 1 wt % doxazosin, 97wt % succinic acid, and 2 wt % PEG 1000. The osmotic pressure of asaturated solution of these tablet excipients was about 29 atm (22 atmosmotic driving force in gastric buffer), and the doxazosin solubilityin a saturated solution of the tablet excipients was about 27 mg/ml.

4) Doxazosin/adipic acid/lactose tablets were made with 1 wt %doxazosin, 10 wt % adipic acid, 79 wt % lactose, and 10 wt % PEG 1000.The osmotic pressure of a saturated solution of these tablet excipientswas about 25 atm (18 atm osmotic driving force in gastric buffer), andthe doxazosin solubility in a saturated solution of the tabletexcipients was about 20 mg/ml. All of the tablets had a total weight of500 mg and contained 5 mg of doxazosin. All of the tablets were coatedwith an asymmetric-membrane coating as described in Example 2.

Release rates from these tablets into gastric buffer vary fromapproximately 0.2 mg/hr to 0.6 mg/hr, as shown in FIG. 7. The releaserates increased with an increase in the osmotic driving force as ischaracteristic of osmotic delivery systems. The release rate from thedoxazosin/adipic acid/lactose tablets was lower than theoreticallypredicted, because the doxazosin solubility was lower than that in theother tablets. Tablets with higher osmotic driving forces will build uplarger boundary layers within the asymmetric membrane, and the releaserates will not be directly proportional to osmotic driving force. Thesedata illustrate that the doxazosin release rates can be controlled byselecting certain soluble fillers for the tablets.

EXAMPLE 11 Formation of Macropores in Asymmetric Membrane

Trimazosin tablets containing 40 wt % trimazosin, 59 wt % Avicel PH102(FMC Corp.), and 1 wt % magnesium stearate with a total weight of 500 mgwere dip-coated as described in Example 2. The coating solutionscontained 1 wt %, 5 wt %, 10 wt %, and 20 wt % glycerol as a pore-formerin place of formamide. All of the coating solutions contained 15 wt %cellulose acetate 398-10 (Eastman Chemical Products, Inc.) and weredissolved in acetone.

The coatings made with these coating solutions were asymmetric instructure and similar to the coatings described in Example 2, butinstead of having a continuous outer skin, macropores were formedthrough the skin. More and slightly larger macropores were formed as theglycerol concentration in the coating solution was increased (FIGS.9-12). Coatings made from coating solutions containing 1 wt % glyceroldo not form macropores through the outer skin, but macropores wereformed on the outer skin as the concentration of glycerol was increasedto 5 wt % glycerol and greater. These macropores, formed during thecoating process, presumably serve as drug-delivery ports.

Trimazosin release rates into water and a 2.4 wt % magnesium sulfatesolution were determined from tablets coated with solutions containing 1wt %, 10 wt %, and 20 wt % glycerol. Higher release rates into waterthan those into the magnesium sulfate solution indicate osmotic release,as was described in Example 6. The release rates into the two receptorsolutions are shown in Table I. The coatings made with 1 wt % and 10 wt% glycerol appeared to deliver trimazosin osmotically (higher releaserates in water than in the magnesium sulfate solution). The releaserates from the tablets coated with the solution containing 20 wt %glycerol were the same into the two receptor solutions, which ischaracteristic of diffusional release. Thus, by controlling the glycerolconcentration in the coating solution, tablet coatings can be made thatfacilitate osmotic and/or diffusional release of the drug.

                  TABLE I                                                         ______________________________________                                                         Released Into                                                                              Released                                        Tablet Coating   2.4-wt % MgSO.sub.4                                                                        Into H.sub.2 O                                  ______________________________________                                        1)    15 wt % CA/1 wt %                                                                            2.41 ± 0.43                                                                             6.30 ± 0.27                                    glycerol/84 wt %                                                              acetone                                                                 2)    15 wt % CA/10 wt %                                                                           4.62 ± 0.54                                                                             7.65 ± 1.05                                    glycerol/75 wt %                                                              acetone                                                                 3)    15 wt % CA/20 wt %                                                                           3.03 ± 2.22                                                                             3.39 ± 0.35                                    glycerol/65 wt %                                                              acetone                                                                 ______________________________________                                    

EXAMPLE 12 Formation of Macropores in Asymmetric Membrane

Trimazosin tablets as described in Example 11 were coated with a coatingsuspension consisting of 15 wt % cellulose acetate 398-10 (EastmanChemical Products, Inc.), 5 wt % sodium acetate and 80 wt % acetone.(The sodium acetate did not dissolve in the coating solution, thus thiscoating solution was a suspension.) The tablets were dip-coated in thestirred coating suspension as described in Example 2. The membranecoatings formed on the tablets were asymmetric and the outer skin hadmany macropores through the surface. These macropores were about 1 μm to5 μm in diameter, as can be seen in FIG. 12. These macropores wereformed during the coating process and could serve as drug delivery portsfor osmotic release.

EXAMPLE 13 Asymmetric Membrane Polymers

Trimazosin tablets containing 40 wt % trimazosin, 58 wt % Ethocel M50(Dow Chemical Co.), and 2 wt % magnesium stearate with a total weight of500 mg were coated with asymmetric membranes made of cellulose acetate398-10 (Eastman Chemical Products, Inc.), Ethocel M50 (Dow ChemicalCo.), and cellulose acetate butyrate 171-15 (FMC Corp.). The tabletswere dip-coated in the same manner as described in Example 2. The threecoating solutions contained 1) 15 wt % cellulose acetate 398-10, and 33wt % ethanol dissolved in acetone; 2) 12 wt % Ethocel M50, 16 wt %formamide, and 24 wt % methanol dissolved in methyl acetate; and 3) 20wt % cellulose acetate butyrate 171-15, 9 wt % acetic acid, and 20 wt %formamide dissolved in acetone.

The trimazosin release rates from all three coated tablets wereconstant, or zero order, for the duration of the tests (7.5 hours),which is typical for osmotic delivery systems. The release rates fromtablets coated with asymmetric cellulose acetate, Ethocel M50, andcellulose acetate butyrate coatings were 3.6±0.2 mg/ml, 0.47±0.11 mg/ml,and 0.22±0.11 mg/ml, respectively. Thus, asymmetric-membrane coatingsthat have different water permeabilities and correspondingly differentdrug release rates.

EXAMPLE 14 Release Rates of Asymmetric Membrane Coated Tablets Preparedby Dry and Wet Processes

Trimazosin release rates into water at 37° C. from the coated tabletsdescribed in Example 3 were compared with those reported in Example 5.The asymmetric cellulose acetate coatings described in Example 3 wereformed by the dry process, that is, a water quench bath was not used. Bycomparison, the tablet coatings described in Example 5 were formed byimmersing the coated tablets in a water quench bath. Trimazosin releaserates from the tablets coated by the dry process were 1.3±0.0 mg/hrcompared with release rates of 4.7±0.4 mg/hr from tablets coated by thequench process. The trimazosin tablets coated by the quench process werelarger (350 mg) than those coated by the dry process (280 mg).Normalizing the release rates with respect to tablet surface areas, therelease rate from the tablets coated by the dry process was 3.9±0.4mg/hr. Thus, the release rate from tablets coated by the dry-processmembranes was about one third that from tablets coated by the quenchprocess. The dry process coatings are evidently less permeable to waterthan are those made by the quench process.

EXAMPLE 15 Asymmetric Membrane Capsules

Capsules have been made with asymmetric-membrane walls. A solution of 15wt % cellulose acetate 398-10 (Eastman Chemical Products, Inc.), and 33wt % ethanol dissolved in acetone was used to make the capsules. Thesolution was kept at room temperature.

Mandrels were made of glass tubes (9 mm and 10 mm outside diameter)fired at one end until they were rounded and had a small hole (about 1mm diameter) in the end. A lactose slurry (2 parts lactose and 1 partwater) was coated on the glass rods then dried to completion.

The mandrels were immersed in the coating solution and withdrawn slowly(5 seconds to completely withdraw the mandrels). The coated mandrelswere inverted and allowed to dry in room-temperature air for 5 secondsand then were immersed in a water quench bath, also at room temperature.The coated mandrels were removed from the water quench bath after 20minutes and the capsules were removed from the mandrels by sliding atightly fitting collar down each mandrel and sliding the capsules off.The capsules were then dried for at least 12 hours in room-temperatureair. The dry capsules were trimmed to size with a razor blade.

Capsules formed by the process described above had walls asymmetric instructure with an overall thickness of about 150 μm. The inside surfaceof the capsules and essentially the entire thickness of the capsule wallwere porous. The dense outer skin was about 1 μm thick, as shown in FIG.13, and was continuous and imperforate.

EXAMPLE 16 Osmotic and Diffusional Release from Asymmetric MembraneCapsules

Asymmetric-membrane capsules were made in the same manner as describedin Example 15. The polymer solution used to make these capsulesconsisted of 17 wt % cellulose acetate 398-10 (Eastman ChemicalProducts, Inc.), and 30 wt % ethanol dissolved in acetone. The capsuleswere soaked in a 20-wt % glycerol solution for at least 12 hours afterthey were removed from the mandrels. The capsules were then allowed todry at room temperature for at least 12 hours. Soaking the capsules inthe glycerol solution plasticized the capsules. Once plasticized, thecapsules remained flexible and resilient for at least six weeks.

The capsules were loaded with 250 mg of a powdered-drug mixture. Thedrug mixture consisted of 1 wt % doxazosin, 10 wt % adipic acid, and 89wt % lactose. The powder was loaded into the body of the capsule, then athin band of adhesive solution was placed around the capsule body suchthat when the cap of the capsule was placed on the body it would coverthe adhesive band. Another band of the adhesive solution was then placedaround the capsule at the joint between the cap and the body. Theadhesive solution was 10 wt % cellulose acetate in ethyl acetate. Theadhesive was allowed to dry for at least two hours before the capsuleswere tested.

The capsules were placed in solutions with different osmotic pressures.The receptor solutions were dextrose solutions of various concentrationsand gastric buffer (described in Example 7). The pH of the dextrosesolutions was adjusted to a pH of 4 by adding tartaric acid. Thedoxazosin solubility in all the dextrose solutions was about 10 mg/ml,and the doxazosin solubility in gastric buffer was about 250 ppm.Release rates from osmotic delivery systems are not dependent on thesolubility of the receptor solution.

The doxazosin release rates from these capsules were higher in solutionshaving lower osmotic pressure, as shown in FIG. 14. The difference inosmotic pressure between the solution inside the capsule and thereceptor solution outside the capsule is the osmotic driving force.Consequently, the osmotic release rates were inversely proportional tothe osmotic pressure of the receptor solution. The osmotic pressureinside the capsule was about 25 atm, so the doxazosin released into the34-atm solution was diffusional rather than osmotic delivery. These dataverify that asymmetric capsules can osmotically deliver drugs and thatthere is a much smaller but significant diffusional contribution to theoverall release of doxazosin.

EXAMPLE 17 Control of Time Lag Before Release from Asymmetric MembraneCapsules

Asymmetric-membrane capsules were made as described in Example 15. Theonly exception to the procedure described in Example 15 was that themandrels used to make the capsules were hard gelatin capsules in placeof glass rods coated with lactose.

The capsules were loaded with three different drug formulations: 1) 300mg of a 40 wt % trimazosin and 60 wt % calcium lactate powder mixture,2) 600 mg slurry of 30 wt % trimazosin in PEG 900 (PEG 900 is a liquidat 37° C. and a solid at room temperature), and 3) 260 mg of a 70 wt %trimazosin and 30 wt % tartaric acid powder mixture. Significantly moreof the trimazosin/PEG 900 slurry could be loaded in the capsules sinceit was a liquid suspension rather than a powder. The capsules weresealed with an epoxy adhesive in the same manner as described in Example16.

These capsules were placed in water at 37° C., and the release oftrimazosin was monitored. Time lags before trimazosin delivery beganwere 7.5 hours, 3 hours, and 0 hours from the capsules loaded with,trimazosin/calcium lactate powder, trimazosin/tartaric acid powder, andtrimazosin/PEG 900 slurry, respectively. A saturated solution oftrimazosin and calcium lactate has a lower osmotic pressure than asaturated solution of trimazosin and tartaric acid, thus a longer timelag from the capsules loaded with trimazosin and calcium lactate wouldbe expected. The rate of water inbibition into the capsules istheoretically proportional to the osmotic pressure within the capsule.The even shorter time lag from capsules loaded with a trimazosin in PEG900 slurry was probably due to a combination of the reduction of theinterstitial volume between the powder particles, better initial contactwith the inside surface of the capsule, and plasticization by the PEG900, which may facilitate quicker wetting of the membrane and a higherwater permeability. The ability to control the time lag before drugdelivery begins may be advantageous for designing drug-delivery systemsthat must be released in the intestines or for other specializeddrug-delivery profiles.

EXAMPLE 18 Macropores in Asymmetric Membrane Capsules

Asymmetric-membrane capsules have been made that have macropores throughthe outer skin of the capsules. These macropores function as drugdelivery ports through which the drug solution is pumped from thecapsules. The capsules were made by the same method as described inExample 15. Gycerol was added to the polymer solution and the ethanolwas removed. The polymer solution consisted of 17 wt % cellulose acetate398-10 (Eastman Chemical Products, Inc.) and 1 wt % to 20 wt % glyceroldissolved in acetone. The macropores were more numerous and slightlylarger as more glycerol was used in the polymer solution and weresimilar in appearance to the macropores in the tablet coatings describedin Example 11. The cross section and surface of a capsule wall made witha 17 wt % cellulose acetate and 3 wt % glycerol solution in acetone isshown in FIG. 15. The macropores through the surface and theinterconnecting pathways through the capsule wall are apparent in theSEM.

Capsules with macropores (such as the formulation described above) havebeen loaded with dextran blue and lactose, then placed in water. Dextranblue delivery from the capsules began within the first hour and waspumped out at a constant rate for several hours. Although the dextranblue cannot actually be seen exiting each macropore, the blue coloraggregates around the exterior of the capsule, and a steady stream flowsto the bottom of the container. In capsules that do not have macroporesthrough the surface, the dextran blue is pumped out discrete deliveryports formed in the asymmetric capsule walls, sometimes with such forcethat a stream of dextran blue is ejected horizontally for more than acentimeter through the water before it flows to the bottom of thecontainer. Thus, macropores can be formed through the outer skin ofasymmetric membrane capsules and appear to function as drug-deliveryports for osmotic drug delivery.

EXAMPLE 19 Asymmetric Membrane Polymers

Asymmetric-membrane capsules have been made with cellulose acetate398-10 (Eastman Chemical Products, Inc.), Ethocel M50 (Dow ChemicalCo.), and cellulose acetate butyrate 171-15 (FMC Corp.). The celluloseacetate capsules were the same as described in Example 15, and theEthocel and cellulose acetate butyrate capsules were made in the samemannner as described in Example 15. The Ethocel polymer solutionconsisted of 12 wt % Ethocel M50, 16 wt % formamide, and 24 wt %methanol dissolved in methyl acetate, and the cellulose acetate butyratepolymer solution consisted of 20 wt % cellulose acetate butyrate, 9 wt %acetic acid, and 20 wt % formamide dissolved in acetone. The averagewall thicknesses of the Ethocel and the cellulose acetate butyratecapsules were approximately 300 μm and 450 μm, respectively. Thethickness of the dense outer skin for both these capsules was about 1μm. All of the capsules were loaded with a 30 wt % trimazosin in PEG 900slurry at about 37° C. (PEG 900 is a solid at room temperature.) Thecapsules were sealed with an epoxy adhesive as described in Example 16.

Trimazosin release rates into water at 37° C. were 7.7±0.2 mg/hr,2.2±0.4 mg/hr, and 0.65±0.4 mg/hr from the capsules made of celluloseacetate, Ethocel, and cellulose acetate butyrate, respectively. Thesedata illustrate the different water permeabilities in the polymersinvestigated and how these properties can be utilized to formulateosmotic capsules with different release kinetics.

EXAMPLE 20 Asymmetric Membrane Coated Beads

Asymmetric membrane coatings were applied to non-pareil beads (20- to25-mesh, or about 1 mm in diameter) with a spray-coating process. Thebeads were mixed with the polymer coating solution, then sprayed throughan external-mixing air-atomizing nozzle (Model 100150) available fromSpraying Systems Co., Wheaton, Ill.

The polymer coating solution consisted of 15 wt % cellulose acetate398-10 (CA, Eastman Chemical Products, Inc.) and a 38-wt % nonsolventmixture dissolved in acetone. The nonsolvent mixture consisted of 57 wt% ethanol, 31 wt % butanol, 7 wt % water, and 5 wt % glycerol.

The beads and polymer solution were mixed just upstream from the spraynozzle, and the mixture of beads and polymer solution was sprayed into aroom kept at about 40° C. As the beads were sprayed into the room, thesolvent evaporated from the beads and an asymmetric-membrane coating wasformed around the beads. Thus, asymmetric-membrane coatings were formedon the beads by a dry process; that is, a quench bath was not requiredto form the asymmetric-membrane coatings. Excess polymer precipitated inflakes, and the beads were separated from the polymer flakes by sieving.Typically, a 7-wt % coating was applied to the beads. The asymmetriccoatings on beads (FIG. 16) were similar in appearance to thedry-process asymmetric-membrane tablet coatings described in Example 3.The asymmetric-membrane coatings on beads were much thinner than thedry-process coatings on tablets. The overall thickness of the coatingson beads was about 10 μm to 20 μm, compared with a thickness of about200 μm on tablets. Coatings formed on both tablets and beads were porousthrough essentially the entire thickness and had a dense outer skin thatwas approximately 1 μm thick.

EXAMPLE 21 Multiple Coatings of Asymmetric Membrane on Beads

Doxazosin beads (20- to 25-mesh) containing 5 wt % doxazosin, 15 wt %Avicel PH101 (FMC Corp.), 9 wt % adipic acid, and 71 wt % lactose wereprepared. In addition, a 2-wt % precoat of 9 parts sucrose and 1 parthydroxypropylmethylcellulose was also applied to these beads. The beadswere coated as described in Example 20 with the polymer solution heatedto 34° C. The coating process was repeated three times, and after eachcoating a quantity of beads were set aside; thus, beads were obtainedwith single, double, and triple coatings. The overall coating thicknessvaried from 5 μm to 15 μm for the single-coated beads, from 10 μm to 25μm for the double-coated beads, and 20 μm to 30 μm for the triple-coatedbeads, as determined by SEM observation. The outer skin of the coatingswas dissolved by the subsequent coatings, leaving a homogeneous porouslayer through the entire coating except for an outer skin that wasapproximately 1 μm thick, as shown by the example in FIG. 17. Theoutside skin was the same for single, double, and triple coatings.

Release rates were determined from these beads (65 mg) into a lactosesolution with an osmotic pressure of 7 atm. The pH of the lactosesolution was lowered to 4 with tartaric acid so the doxazosin solubilitywould be the same as in water (10 mg/ml). Release rates were lower frombeads that were coated more times, as shown in FIG. 18. This wasprobably due to the increase in overall thickness of the asymmetriccoating as additional coatings were applied.

EXAMPLE 22 Osmotic Release from Asymmetric Membrane Coated Beads

Triple-coated doxazosin beads, as described in Example 21, were releasedinto receptor solutions of differing osmotic pressures. The beads werereleased into water (osmotic pressure of 0 atm), a lactose solution withan osmotic pressure of 7 atm, and a dextrose solution with an osmoticpressure of 20 atm. Tartaric acid was added to the lactose and dextrosesolutions to adjust the pH to 4 so that the doxazosin solubility, 10mg/ml, would be the same in these sugar solutions as it was in water.Thus, any differences in release rates from the beads into the differentreceptor solutions will not be due to different concentration gradientsacross the membrane coatings, and the diffusional contribution to thedrug release from the beads is the same in all cases. Thedoxazosin-release rates into these three receptor solutions are shown inFIG. 19. Approximately 0.6 mg of doxazosin was released at different,constant rates from 65 mg of beads placed in each of the receptorsolutions. Presumably, the soluble fillers were almost completelyreleased at the point when 0.6 mg of doxazosin had been released,decreasing the osmotic driving force and the doxazosin-release rate. Thedependence of the release rates on the osmotic pressure, or moreprecisely, the difference in osmotic pressure between the solutioninside of the beads and the receptor solution is characteristic ofosmotic release.

EXAMPLE 23 Formation of Macropores in Assymmetric Membrane Coated Beads

Asymmetric-membrane coatings have been applied to non-pareils by mixingthe beads (20- to 25-mesh) in a polymer coating solution at roomtemperature (same polymer coating solution as that described in Example20). The beads and coating solution were placed in a pressure vessel,and 40 psi was applied to the vessel. The beads and polymer solutionwere sprayed out an airless nozzle (a hose connector with a 3-mmdiameter oriface) into room-temperature air. The sudden pressure drop asthe beads and the coating were sprayed out the nozzle caused bubbles toform in the coating solution, thus forming macropores through the outerskin as the coating precipitates (FIG. 20). The same coating solution(and conditions) but applied without a pressure drop forms a continuous,dense outer skin, as described in Example 3.

EXAMPLE 24 Formation of Asymmetric Membrane Coated Beads-Wet Process

Trimazosin beads (18- to 20-mesh), containing 30 wt % trimazosin and 70wt % Avicel PH101 (FMC Corp.) were mixed with a polymer coating solutionand dripped into a water quench bath to form asymmetric osmotic beads.The polymer coating solution was made of 15 wt % cellulose acetate398-10 (Eastman Chemical Products, Inc.), and 33 wt % ethanol dissolvedin acetone and was used at room temperature. A mixture of beads andcoating solution was dripped into a water quench bath at roomtemperature from a disposable pipet tip, forming large, sphericalasymmetric beads that could contain from none to several smallertrimazosin beads. The beads were kept in the water quench bath for abouta minute then removed and allowed to air-dry at room temperature for atleast 12 hours. These asymmetric beads had diameters of 2 to 3 mm and askinned outer surface. Inside the particles was a porous celluloseacetate network. Any trimazosin beads present were dispersed in theporous cellulose acetate network. Osmotic release of trimazosin fromthese beads was demonstrated by submerging these beads in water and in a4 wt % magnesium sulfate solution. The results are shown in FIG. 21. Thesolubility of trimazosin is the same in both solutions; thus, the 75%decrease in release rate into the magnesium sulfate solution was due toreduction of the osmotic driving force across the membrane coating,demonstrating osmotic release.

EXAMPLE 25 Formation of Macropores in Asymmetric Membranes

Doxazosin tablets containing 1.7 wt % doxazosin, 10 wt % adipic acid, 10wt % PEG 3350, and 78.3 wt % lactose (total weight of 150 mg) weredip-coated with a solution consisting of 15 wt % CA 398-10, 30 wt %ethanol, and 55 wt % acetone. The coated tablets were air-dried for 5seconds and then immersed in a 60° C. water quench bath for 5 minutes.After the coated tablets were removed from the quench bath, they wereair-dried for at least 12 hours at ambient temperature and humidity.These membrane coatings were asymmetric and had macropores in the outersurface of the coating. Small bubbles could be seen forming on thesurface of the membrane coating as it precipitated in the quench bath.Several of these bubbles ruptured the skin of the membrane coatingforming macropores that could serve as drug-delivery ports.

EXAMPLE 26 Formation of Macropores in Asymmetric Membranes

Doxazosin tablets as described in Example 25 were dip-coated with asolution consisting of 15 wt % CA 398-10, 30 wt % ethanol, and 55 wt %acetone. The coated tablets were air-dried for 5 seconds and thenimmersed in an ethanol quench bath at ambient temperature for 5 minutes.After the tablets were removed from the quench bath, they were air-driedfor at least 12 hours at ambient conditions. The membrane coatings wereasymmetric and the outer skin had many macropores through the surface.These macropores were about 1 μm in diameter. The macropores were formedduring the coating process and could serve as drug delivery ports.

EXAMPLE 27 Formation of Asymmetric-Membrane Capsules Made WithEthylcellulose

Capsules with asymmetric-membrane walls were made from a coatingsolution of 15 wt % ethylcellulose (Ethocel std-45, Dow Chemical,Midland, Mich.), 25 wt % acetic acid, and 5 wt % glycerol dissolved inacetone.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed in 40°C. coating solution and were withdrawn slowly, taking 7 seconds tocompletely withdraw the mandrels. The coated mandrels were exposed toroom-temperature air for 30 seconds and then immersed in a 45° C. quenchbath that contained 5 wt % glycerol in water. The coated mandrels wereremoved from the quench bath after 30 minutes, and the capsule caps andbodies were removed from the mandrels by sliding a tight collar downeach mandrel to force the caps and bodies off the mandrels. The capsulecaps and bodies were dried in room-temperature air for at least 12 hoursand then trimmed to the desired lengths.

Capsules formed by the process described above had walls about 200 μmthick that were asymmetric in structure. Essentially the entirethickness of the capsule wall, including the inside surface of thecapsule, was porous. The dense outer skin was less than 1 μm thick and,as shown in FIG. 22, was continuous and imperforate.

These capsules were loaded with 200 mg of a powder mixture thatcontained 5 wt % glipizide (a diabetes drug) and 95 wt % tromethamine.The loaded capsules were sealed at the junction of the trimmed end ofthe cap and the capsule body with a narrow band of solution thatcontained 15 wt % cellulose acetate (CA 398-10, Eastman Chemicals,Kingsport, Tenn.), 8 wt % glycerol, and 25 wt % ethanol dissolved inacetone. The volatile solvents were evaporated, leaving a celluloseacetate seal that prevented the capsule cap and body from separatingduring release-rate tests.

For release-rate tests, the loaded capsules were placed in a stirredsolution of simulated intestinal buffer (osmotic pressure of 7 atm andpH of 7.5) at 37° C. About 70% of the glipizide was released at aconstant rate--a release pattern that is typical of osmotic-deliverysystems. The steady-state release rate of glipizide (during the periodof constant release) was 0.63±0.08 mg/hr.

EXAMPLE 28 Formation of Asymmetric-Membrane Capsules Made With CelluloseAcetate Butyrate

Capsules with asymmetric-membrane walls were made from a coatingsolution of 15 wt % cellulose acetate butyrate (CAB 381-20, EastmanChemicals, Kingsport, Tenn.), 30 wt % ethanol, and 5 wt % glyceroldissolved in acetone.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were withdrawn slowly, taking 9seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained 5 wt % glycerol in water.The coated mandrels were removed from the quench bath after 30 minutes,and the capsule caps and bodies removed from the mandrels by sliding atight collar down each mandrel to force the caps and bodies off themandrels. The capsule caps and bodies were dried in room-temperature airfor at least 12 hours and then trimmed to the desired lengths.

Capsules formed by the process described above had walls about 250 μmthick that were asymmetric in structure. Essentially the entirethickness of the capsule wall, including the inside surface of thecapsules, was porous. The dense outer skin was less than 1 μm thick and,as shown in FIG. 23, was continuous and imperforate.

These capsules were loaded with 200 mg of a powder mixture thatcontained 10 wt % glipizide (a diabetes drug) and 90 wt % tromethamine.The loaded capsules were sealed at the junction of the trimmed end ofthe cap and the capsule body with a narrow band of a solution thatcontained 15 wt % cellulose acetate (CA 398-10, Eastman Chemicals,Kingsport, Tenn.), 8 wt % glycerol, and 25 wt % ethanol dissolved inacetone. The volatile solvents were evaporated, leaving a celluloseacetate seal that prevented the capsule cap and body from separatingduring release-rate tests.

For release-rate tests, the loaded capsules were placed in a stirredsolution of simulated intestinal buffer (osmotic pressure of 7 atm andpH of 7.5) at 37° C. About 70% of the glipizide was released at aconstant rate--a release pattern typical of osmotic-delivery systems.The steady-state release rate of glipizide (during the period ofconstant release) was 1.60±0.15 mg/hr.

EXAMPLE 29 Formation of Asymmetric-Membrane Capsules Made With A Blendof Ethylcellulose and Cellulose Acetate

Capsules with asymmetric-membrane walls were made from a coatingsolution of 10 wt % ethylcellulose (Ethocel std-100, Dow Chemical,Midland, Mich.), 2 wt % cellulose acetate (CA 398-10, Eastman Chemicals,Kingsport, Tenn.), 30 wt % ethanol, and 10 wt % glycerol dissolved inacetone.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were withdrawn slowly, taking 9seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained 5 wt % glycerol in water.The coated mandrels were removed from the quench bath after 30 minutes,and the capsule caps and bodies removed from the mandrels by sliding atight collar down each mandrel to force the caps and bodies off themandrels. The capsule caps and bodies were dried in room-temperature airfor at least 12 hours and then trimmed to the desired lengths.

Capsules formed by the process described above had walls about 200 μmthick that were-asymmetric in structure. Scanning electronmicrophotographs (SEMs) showed that in some areas CA had separated fromthe Ethocel, forming dispersed spheres throughout the membrane, as shownin FIG. 24. The incompatibility between the two polymers also causedmacropores to form in the surface of the membrane. These macropores canfunction as drug-delivery ports. Thus, blending two incompatiblepolymers can be used to form asymmetric-membrane capsules or coatingsthat contain macropores in the surface.

These capsules were loaded with 200 mg of a powder mixture thatcontained 10 wt % glipizide (a diabetes drug) and 90 wt %N-methylglucamine. The loaded capsules were sealed at the junction ofthe trimmed end of the cap and capsule body with a narrow band of asolution that contained 15 wt % cellulose acetate (CA 398-10, EastmanChemicals, Kingsport, Tenn.), 8 wt % glycerol, and 25 wt % ethanoldissolved in acetone. The volatile solvents were evaporated, leaving acellulose acetate seal that prevented the capsule cap and body fromseparating during release-rate tests.

For release-rate tests, the loaded capsules were placed in a stirredsolution of simulated intestinal buffer (osmotic pressure of 7 atm andpH of 7.5) at 37° C. About 70% of the glipizide was released at aconstant rate--a release pattern that is typical of osmotic-deliverysystems. The steady-state release rate of glipizide (during the periodof constant release) was 2.2±0.2 mg/hr.

EXAMPLE 30 Formation of Asymmetric-Membrane Capsules Made With A Blendof Cellulose Acetate Butyrate Ethylcellulose

Capsules with asymmetric-membrane walls were made from a coatingsolution of 13 wt % cellulose acetate butyrate (CAB 381-20, EastmanChemicals, Kingsport, Tenn.), 2 wt % ethylcellulose (Ethocel std-100,Dow Chemical, Midland, Mich.), 30 wt % ethanol, and 5 wt % glyceroldissolved in acetone.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were then withdrawn slowly, taking7 seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained 5 wt % glycerol in water.The coated mandrels were removed from the quench bath after 30 minutes,and the capsule bodies and caps were removed from the mandrels bysliding a tight collar down each mandrel to force the caps and bodiesoff the mandrels. The capsule bodies and caps were dried inroom-temperature air for at least 12 hours and then trimmed to thedesired lengths.

Capsule bodies and caps formed by the process described above had wallsabout 200 μm thick that were asymmetric in structure. Essentially theentire thickness of the capsule wall, including the inside surface ofthe capsule, was porous. The dense outer skin was less than 1 μm thickand had many dimples, as shown in FIG. 25. The dimples appear to containmacropores in the outer skin, which could serve as drug-delivery ports.

The capsules were loaded with 200 mg of a powder mixture that contained10 wt % glipizide (a diabetes drug) and 90 wt % N-methylglucamine. Theloaded capsules were sealed at the junction of the end of the cap andthe capsule body with a narrow band of a solution containing 15 wt %cellulose acetate (CA 398-10, Eastman Chemical, Kingsport, Tenn.), 8 wt% glycerol, and 25 wt % ethanol dissolved in acetone. The volatilesolvents were evaporated, leaving a cellulose acetate seal thatprevented the capsule cap and body from separating during release-ratetests.

For release-rate tests, loaded capsules were placed in a stirredsolution of simulated intestinal buffer (osmotic pressure of 7 atm andpH of 7.5) at 37° C. About 70% of the glipizide was release at aconstant rate--a release pattern that is typical of osmotic-deliverysystems. The steady-state release rate of glipizide (during the periodof constant release) was 1.25±0.05 mg/hr.

EXAMPLE 31 Formation of Asymmetric-Membrane Capsules Made With A Blendof Cellulose Acetate Butyrate and Cellulose Acetate

Capsules with asymmetric-membrane walls were made from a coatingsolution of 12 wt % cellulose acetate butyrate (CAB 381-20, EastmanChemicals, Kingsport, Tenn.), 3 wt % cellulose acetate (CA 398-10,Eastman Chemicals, Kingsport, Tenn.), 30 wt % ethanol, and 5 wt %glycerol dissolved in acetone.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed in 12°C. coating solution and were withdrawn slowly, taking 7 seconds tocompletely withdraw the mandrels. The coated mandrels were exposed toroom-temperature air for 7 seconds and then immersed in a 42° C. quenchbath that contained 5 wt % glycerol in water. The coated mandrels wereremoved from the quench bath after 30 minutes, and the capsule caps andbodies removed from the mandrels by sliding a tight collar down eachmandrel to force the caps and bodies off the mandrels. The capsule capsand bodies were dried in room-temperature air for at least 12 hours andthen trimmed to the desired lengths.

Capsule bodies and caps formed by the process described above had wallsabout 300 μm thick that were asymmetric in structure. Essentially theentire thickness of the capsule wall, including the inside surface ofthe capsule, was porous. The dense outer skin was less than 1 μm thickand, as shown in FIG. 26, was continuous and imperforate.

The capsules were loaded with 200 mg of a powder mixture that containedof 10 wt % glipizide (an anti-diabetes drug) and 90 wt %N-methylglucamine. The loaded capsules were sealed at the junction ofthe trimmed end of the cap and the capsule body with a narrow band of asolution containing 15 wt % cellulose acetate (CA 398-10, EastmanChemicals, Kingsport, Tenn.), 8 wt % glycerol, and 25% ethanol dissolvedin acetate. The volatile solvents were evaporated, leaving a celluloseacetate seal that prevented the capsule cap and body from separatingduring release-rate tests.

For release-rate tests, loaded capsules were placed in a stirredsolution of simulated intestinal buffer (osmotic pressure of 7 atm andpH of 7.5) at 7° C. About 70% of the glipizide was released at aconstant rate--a release pattern that is typical of osmotic-deliverysystems. The steady-state release rate of glipizide (during the periodof constant release) was 2.91±0.22 mg/hr.

EXAMPLE 32 Formation of Asymmetric-Membrane Capsules Made With CelluloseAcetate Propionate

Capsules with asymmetric-membrane walls were made from a solution of 34wt % cellulose acetate propionate (CAP 482-0.5, Eastman Chemicals,Kingsport, Tenn.), and 10 wt % glycerol dissolved in acetone.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were withdrawn slowly, taking 9seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 3 seconds and then immersed in aroom-temperature quench bath that contained 15 wt % glycerol in water.The coated mandrels were removed from the quench bath after 30 minutes,and the capsule caps and bodies were removed from the mandrels bysliding a tight collar down each mandrel to force the caps and bodiesoff the mandrels. The capsule caps and bodies were trimmed to thedesired lengths and then dried in room-temperature air for at least 12hours.

Capsules formed by the process described above had walls about 450 μmthick that were asymmetric in structure. Essentially the entirethickness of the capsule walls, including the inside surface of thecapsules, was porous, as shown in FIG. 27. The dense outer skin was lessthan 1 μm thick and contained many macro-pores, which would function asdrug-delivery ports.

EXAMPLE 33 Formation of Asymmetric-Membrane Capsules Made WithNitrocellulose

Capsules with asymmetric-membrane walls were made from a solution of36.5 wt % nitrocellulose (nitrocellulose RS 18-25, Hercules, Inc.,Wilmington, Del.), 13.5 wt % isopropanol, and 15 wt % glycerol dissolvedin acetone.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were then withdrawn slowly, taking10 seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained 15 wt % glycerol in water.The coated mandrels were removed from the quench bath after 30 minutes,and the capsule caps and bodies were removed from the mandrels bysliding a tight collar down each mandrel to force the caps and bodiesoff the mandrels. The capsule caps and bodies were dried inroom-temperature air for at least 12 hours and then trimmed to thedesired lengths.

Capsules formed by the process described above had walls about 400 μmthick that were asymmetric in structure. Essentially the entirethickness of the capsule walls, including the inside surface of thecapsules, was porous, as shown in FIG. 28. The dense outer skin was lessthan 1 μm thick.

EXAMPLE 34 Formation of Asymmetric-Membrane Capsules Made With CelluloseAcetate Phthalate

Capsules with asymmetric-membrane walls were made from a solution of23.6 wt % cellulose acetate phthalate (CAPh, Eastman Chemicals,Kingsport, Tenn.), 25.5 wt % ethanol, and 7.3 wt % glycerol dissolved inacetone.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were withdrawn slowly, taking 7seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained water acidified with a fewdrops of sulfuric acid. The coated mandrels were removed from the quenchbath after 30 minutes, and the capsule caps and bodies were removed fromthe mandrels by sliding a tight collar down each mandrel to force thecaps and bodies off the mandrels. The capsule caps and bodies were driedin room-temperature air for at least 12 hours and then trimmed to thedesired lengths.

Capsules formed by the process described above had walls about 200 μmthick that were asymmetric in structure. Essentially the entirethickness of the capsule walls, including the inside surface of thecapsules, was porous, as shown in FIG. 29. The dense outer skin was lessthan 1 μm thick and was continuous and imperforate.

EXAMPLE 36 Formation of Asymmetric-Membrane Capsules Made With PolyvinylAlcohol

Capsules with asymmetric-membrane walls were made from a coatingsolution of 15 wt % polyvinyl alcohol (Elvanol 71-30, Dupont,Wilmington, Del.), and 20 wt % ethanol dissolved in water.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed in 70°C. coating solution and were withdrawn slowly, taking 10 seconds tocompletely withdraw the mandrels. The coated mandrels were exposed toroom-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained 70 wt % acetone and 30 wt %water. The coated mandrels were removed from the quench bath after 30minutes, and the capsule caps and bodies were removed from the mandrelsby sliding a tight collar down each mandrel to force the caps and bodiesoff the mandrels. The capsule caps and bodies were dried inroom-temperature air for at least 12 hours and then trimmed to thedesired lengths.

Capsules formed by the process described above had walls about 350 μmthick that were asymmetric in structure. Most of the thickness of thecapsule walls, including the inside surface of the capsules, was porous,as shown in FIG. 31. The dense outer skin was approximately 50 μm thickand continuous and imperforate.

These capsules were loaded with 200 mg of a powder mixture thatcontained 10 wt % glipizide (a diabetes drug) and 90 wt %N-methylglucamine. The loaded capsules were sealed at the junction ofthe trimmed end of the cap and the capsule body with a narrow band of asolution that contained 15 wt % cellulose acetate (CA 398-10, EastmanChemicals, Kingsport, Tenn.), 8 wt % glycerol, and 25 wt % ethanoldissolved in acetone. The volatile solvents were evaporated, leaving acellulose acetate seal that prevented the capsule cap and body fromseparating during release-rate tests.

For release-rate tests, loaded capsules were placed in a stirredsolution of simulated intestinal buffer (osmotic pressure of 7 atm andpH of 7.5) at 37° C. About 90% of the glipizide was released at aconstant rate--a release pattern typical of osmotic-delivery systems.The steady-state release rate of glipizide (during the period ofconstant release) was 6.04±0.48 mg/hr.

EXAMPLE 37 Formation of Asymmetric-Membrane Capsules Made WithEthylenevinyl Alcohol

Capsules with asymmetric-membrane walls were made from a coatingsolution of 15 wt % ethylenevinyl alcohol (EVAL F-101, EVAL Co. ofAmerica, Omaha, Nebr.), 55 wt % ethanol, and 30 wt % water.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed in 40°C. coating solution and were withdrawn slowly, taking 7 seconds tocompletely withdraw the mandrels. The coated mandrels were exposed toroom-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained water. The coated mandrelswere removed from the quench bath after 30 minutes, and the capsule capsand bodies were removed from the mandrels by sliding a tight collar downeach mandrel to force the caps and bodies off the mandrels. The capsulecaps and bodies were dried in room-temperature air for at least 12 hoursand then trimmed to the desired lengths.

Capsules formed by the process described above had walls about 200 μmthick that were asymmetric in structure. Essentially the entirethickness of the capsule walls, including the inside surface of thecapsules, was porous, as shown in FIG. 32. The dense outer skin was lessthan 1 μm thick and was continuous and imperforate.

These capsules were loaded with 200 mg of a powder mixture thatcontained 10 wt % glipizide (a diabetes drug) and 90 wt % tromethamine.The loaded capsules were sealed at the junction of the trimmed end ofthe cap and the capsule body with a narrow band of a solution thatcontained 15 wt % cellulose acetate (CA 398-10, Eastman Chemicals,Kingsport, Tenn.), 8 wt % glycerol, and 25 wt % ethanol dissolved inacetone. The volatile solvents were evaporated, leaving a celluloseacetate seal that prevented the capsule cap and body from separatingduring release-rate tests.

For release-rate tests, loaded capsules were placed in a stirredsolution of simulated intestinal buffer (osmotic pressure of 7 atm andpH of 7.5) at 37° C. About 70% of the glipizide was released at aconstant rate--a release pattern that is typical of osmotic-deliverysystems. The steady-state release rate of glipizide (during the periodof constant release) was 6.47±0.31 mg/hr.

EXAMPLE 38 Formation of Asymmetric-Membrane Capsules Made WithPolyurethane

Capsules with asymmetric-membrane walls were made from a coatingsolution of 24.5 wt % polyurethane (Tuftane 310, Lord Corp, Erie, Pa.)dissolved in dimethylformamide.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were withdrawn slowly, taking 11seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained water. The coated mandrelswere removed from the quench bath after 30 minutes, and the capsule capsand bodies were removed from the mandrels by sliding a tight collar downeach mandrel to force the caps and bodies of the mandrels. The capsulecaps and bodies were dried in room-temperature air for at least 12 hoursand then trimmed to the desired lengths.

Capsules formed by the process described above had walls about 200 μmthick that were asymmetric in structure. Essentially the entirethickness of the capsule walls, including the inside surface of thecapsules, was porous, as shown in FIG. 33. The dense outer skin was lessthan 1 μm thick and was continuous and imperforate.

These capsules were loaded with 200 mg of a powder mixture thatcontained 10 wt % glipizide (a diabetes drug) and 90 wt %N-methylglucamine. The loaded capsules were sealed at the junction ofthe trimmed end of the cap and the capsule body with a narrow band of asolution containing 15 wt % cellulose acetate (CA 398-10, EastmanChemicals, Kingsport, Tenn.), 8 wt % glycerol, and 25 wt % ethanoldissolved in acetone. The volatile solvents were evaporated, leaving acellulose acetate seal that prevented the capsule cap and body fromseparating during release-rate tests.

For release-rate tests, loaded capsules were placed in a stirredsolution of simulated intestinal buffer (osmotic pressure of 7 atm andpH of 7.5) at 37° C. About 70% of the glipizide was released at aconstant rate--a release pattern that is typical of osmotic-deliverysystems. The steady-state release rate of glipizide (during the periodof constant release) was 0.62±0.04 mg/hr.

EXAMPLE 39 Formation of Asymmetric-Membrane Capsules Made WithPolyvinylidene Fluoride

Capsules with asymmetric-membrane walls were made from a coatingsolution of 15 wt % polyvinylidene fluoride (Kynar 460, Pennwalt Corp.,Philadelphia, Pa.) dissolved in dimethylformamide.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom temperature coating solution and were withdrawn slowly, taking 7seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained water. The coated mandrelswere removed from the quench bath after 30 minutes, and the capsule capsand bodies were removed from the mandrels by sliding a tight collar downeach mandrel to force the caps and bodies off the mandrels. The capsulecaps and bodies were dried in room-temperature air for at least 12 hoursand then trimmed to the desired lengths.

Capsules formed by the process described above had walls about 100 μmthick that were asymmetric in structure. Essentially the entirethickness of the capsule walls, including the inner surface of thecapsules, was porous, as shown in FIG. 34. The outer skin was coveredwith many pores less than 1 μm in diameter.

These capsules were loaded with 200 mg of a powder mixture thatcontained 10 wt % glipizide (a diabetes drug) and 90 wt %N-methylglucamine. The loaded capsules were sealed at the junction ofthe trimmed end of the cap and the capsule body with a narrow band of asolution that contained 15 wt % cellulose acetate (CA 398-10, EastmanChemicals, Kingsport, Tenn.), 8 wt % glycerol, and 25 wt % ethanoldissolved in acetone. The volatile solvents were evaporated, leaving acellulose acetate seal that prevented the capsule cap and body fromseparating during release-rate tests.

For release-rate tests, loaded capsules were placed in a stirredsolution of simulated intestinal buffer (osmotic pressure of 7 atm andpH of 7.5) at 37° C. About 70% of the glipizide was released at aconstant rate--a release pattern that is typical of osmotic-deliverysystems. The steady-state release rate of glipizide (during the periodof constant release) was 0.67±0.06 mg/hr.

EXAMPLE 40 Formation of Asymmetric-Membrane Capsules Made WithPolysulfone

Capsules with asymmetric-membrane walls were made from a coatingsolution of 21.4 wt % polysulfone (Udel 1700, Union Carbide, Danbury,Conn.) dissolved in dimethylformamide.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were withdrawn slowly, taking 4seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained water. The coated mandrelswere removed from the quench bath after 30 minutes, and the capsule capsand bodies were removed from the mandrels by sliding a tight collar downeach mandrel to force the caps and bodies off the mandrels. The capsulecaps and bodies were dried in room-temperature air for at least 12 hoursand then trimmed to the desired lengths.

Capsules formed by the process described above had walls about 150 μmthick that were asymmetric in structure. Essentially the entirethickness of the capsule walls, including the inside surface of thecapsule, was porous, as shown in FIG. 35. The dense outer skin was lessthan 1 μm thick and was continuous and imperforate.

These capsules were loaded with 200 mg of a powder mixture thatcontained 10 wt % glipizide (a diabetes drug) and 90 wt %N-methylglucamine. The loaded capsules were sealed at the junction ofthe trimmed end of the cap and the capsule body with a narrow band of asolution that contained 15 wt % cellulose acetate (CA 398-10, EastmanChemicals, Kingsport, Tenn.), 8 wt % glycerol, and 25 wt % ethanoldissolved in acetone. The volatile solvents were evaporated, leaving acellulose acetate seal that prevented the capsule cap and body fromseparating during release-rate tests.

For release-rate tests, loaded capsules were placed in a stirredsolution of simulated intestinal buffer (osmotic pressure of 7 atm andpH of 7.5) at 37° C. The steady-state release rate of glipizide (duringthe period of constant release) was 0.42±0.03 mg/hr.

EXAMPLE 41 Formation of Asymmetric-Membrane Capsules Made WithPolymethyl Methacrylate

Capsules with asymmetric-membrane walls were made from a coatingsolution of 25 wt % polymethyl methacrylate (PMMA V-920, Rohm and Haas,Philadelphia, Pa.), and 10 wt % polyethylene glycol dissolved inacetone.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were withdrawn slowly, taking 7seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 10 seconds and then immersed in aroom-temperature quench bath that contained water. The coated mandrelswere removed from the quench bath after 30 minutes, and the capsule capsand bodies were removed from the mandrels by sliding a tight collar downeach mandrel to force the caps and bodies off the mandrels. The capsulecaps and bodies were dried in room-temperature air for at least 12 hoursand then trimmed to the desired lengths.

Capsules formed by the process described above had walls about 200 μmthick that were asymmetric in structure. Most of the thickness of thecapsule walls, including the inside surface of the capsules, was porous,as shown in FIG. 36. The dense outer skin was about 5 μm thick and wascontinuous and imperforate.

EXAMPLE 42 Formation of Asymmetric-Membrane Capsules Made With Polyamide

Capsules with asymmetric-membrane walls were made from a coatingsolution of 25 wt % polyamide (Elvamide 8063, Dupont, Wilmington, Del.),19 wt % water, and 56 wt % ethanol.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were withdrawn slowly, taking 20seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained water. The coated mandrelswere removed from the quench bath after 30 minutes, and the capsule capsand bodies were removed from the mandrels by sliding a tight collar downeach mandrel to force the caps and bodies off the mandrels. The capsulecaps and bodies were dried in room-temperature air for at least 12 hoursand then trimmed to the desired lengths.

Capsules formed by the process described above had walls about 100 μmthick that were asymmetric in structure. Most of the thickness of thecapsule walls, including the inside surface of the capsules, was porous,as shown in FIG. 37. The dense outer skin was about 11 μm thick and wascontinuous and imperforate.

These capsules were loaded with 200 mg of a powder mixture thatcontained 10 wt % glipizide (a diabetes drug) and 90 wt %N-methylglucamine. The loaded capsules were sealed at the junction ofthe trimmed end of the cap and the capsule body with a narrow band of asolution that contained 15 wt % cellulose acetate (CA 398-10, EastmanChemicals, Kingsport, Tenn.), 8 wt % glycerol, and 25 wt % ethanoldissolved in acetone. The volatile solvents were evaporated, leaving acellulose acetate seal that prevented the capsule cap and body fromseparating during release-rate tests.

For release-rate tests, loaded capsules were placed in a stirredsolution of simulated intestinal buffer (osmotic pressure of 7 atm andpH of 7.5) at 37° C. The steady-state release rate of glipizide (duringthe period of constant release) was 0.10±0.03 mg/hr.

EXAMPLE 43 Formation of Asymmetric-Membrane Capsules Made With A Blendof Ethylcellulose and Cellulose Acetate Phthalate

Capsules with asymmetric-membrane walls were made from a coatingsolution of 10 wt % ethylcellulose (Ethocel std-100, Dow Chemicals,Midland, Mich.), 2 wt % cellulose acetate phthalate (CAPh, EastmanChemicals, Kingsport, Tenn.), 30 wt % ethanol, and 10 wt % glyceroldissolved in acetone.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were withdrawn slowly, taking 9seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained 5 wt % glycerol in water.The coated mandrels were removed from the quench bath after 30 minutes,and the capsule caps and bodies were removed from the mandrels bysliding a tight collar down each mandrel to force the caps and bodiesoff the mandrels. The capsule caps and bodies were dried inroom-temperature air for at least 12 hours and then trimmed to thedesired lengths.

Capsules formed by the process described above had walls about 250 μmthick that were asymmetric in structure. Essentially the entirethickness of the capsule walls, including the inner surface of thecapsules, was porous, as shown in FIG. 38. The dense outer skin hadmacropores on the surface, which could serve as drug-delivery ports. Themacropores were typically less than 1 μm in diameter.

EXAMPLE 44 Formation of Asymmetric-Membrane Capsules Made With A Blendof Ethylcellulose and Cellulose Acetate Trimellitate

Capsules with asymmetric-membrane walls were made from a coatingsolution of 10 wt % ethylcellulose (Ethocel std-100, Dow Chemicals,Midland, Mich.), 2 wt % cellulose acetate trimellitate (CAT, EastmanChemicals, Kingsport, Tenn.), 30 wt % ethanol, and 10 wt % glyceroldissolved in acetone.

Capsules were made using two sizes of mandrels--one size for the capsulecap and one size for the capsule body. The mandrels were immersed inroom-temperature coating solution and were withdrawn slowly, taking9.seconds to completely withdraw the mandrels. The coated mandrels wereexposed to room-temperature air for 7 seconds and then immersed in aroom-temperature quench bath that contained 5 wt % glycerol in water.The coated mandrels were removed from the quench bath after 30 minutes,and the capsule caps and bodies were removed from the mandrels bysliding a tight collar down each mandrel to force the caps and bodiesoff the mandrels. The capsule caps and bodies were dried inroom-temperature air for at least 12 hours and then trimmed to thedesired lengths.

Capsules formed by the process described above had walls about 250 μmthick that were asymmetric in structure. Essentially the entirethickness of the capsule walls, including the inside surface of thecapsules, was porous, as shown in FIG. 39. The dense outer skin appearedto have macropores through the surface, which could serve asdrug-delivery ports. The macropores were typically less than 1 μm indiameter.

EXAMPLE 45 Asymmetric-Membrane Coatings Made Of Ethylcellulose OnDrug-Containing Beads

Asymmetric-membrane coatings were applied to drug-containing beads (30to 35 mesh, less than 1 mm in diameter) with the spray-coating processdescribed in Examples 20 and 21 from the original patent application.The beads consisted of 11 wt % glipizide (a diabetes drug), 36 wt %sodium bicarbonate, 48 wt % N-methylglucamine and 5 wt % carboxymethylcellulose.

The polymer solution contained 11 wt % ethylcellulose (Ethocel std-100,Dow Chemicals, Midland, Mich.), 14 wt % water, and 75 wt % acetone. Thepolymer solution was kept at 40° C. and the drying chamber was kept at70° C. The beads were mixed with the polymer solution just upstream fromthe spray nozzle and the mixture was sprayed into the drying chamber toevaporate the solvent and to form the asymmetric coatings. The coatingprocess was repeated (as described in Example 21) to apply a secondasymmetric-membrane coating to the beads.

The double-coated beads were covered with an asymmetric-membrane coatingthat was approximately 15 μm thick. The entire thickness of the coatingwas porous except for a dense outer skin, as shown in FIG. 40. The denseouter skin was less than 1 μm thick and was continuous and imperforateover the entire surface of the beads.

EXAMPLE 46 Asymmetric-Membrane Coatings Made of Cellulose AcetateButyrate On Drug-Containing Beads

Asymmetric-membrane coatings were applied to drug-containing beads (30to 40 mesh, less than 1 mm in diameter) using the spray-coating processdescribed in Examples 20 and 21. The beads were made using 11 wt %glipizide (a diabetes drug), 35 wt % lactose, 35 wt % cornstarch, 11 wt% N-methylglucamine, 5 wt % carboxymethyl cellulose and 3 wt %microcrystalline cellulose.

The polymer solution consisted of 31 wt % cellulose acetate butyrate(CAB 500-1, FMC Corp., Newark, Del.), 14 wt % methyl ethyl ketone, 3 wt% water and 52 wt % acetone. The polymer solution was kept at 45° C. andthe drying chamber was kept at 80° C. The beads were mixed with thepolymer solution just upstream from the spray nozzle and the mixture wassprayed into the drying chamber to evaporate the solvent and form theasymmetric coatings. The coating process (as described in Example 21)was repeated to apply a second asymmetric-membrane coating to the beads.

The double-coated beads were covered with an asymmetric-membrane coatingthat was approximately 20 μm thick. Except for a dense outer skin, theentire thickness of the coating was porous, as shown in FIG. 41. Thedense outer skin was less than 1 μm thick and was continuous andimperforate over the entire surface of the beads.

EXAMPLE 47 Water Fluxes Through Asymmetric-Membrane Capsule WallsCorrespond to Drug-Release Rates

Capsules with asymmetric-membrane walls were made with several differentpolymers, including polyvinyl alcohol (PVA), polyvinylidene fluoride(PVDF), and blends of cellulose acetate butyrate (CAB) and celluloseacetate; CAB and ethylcellulose (Ethocel); and Ethocel and CA. Thecapsules were made as described in Examples 29, 30, 31, 36 and 39.

To determine water fluxes for each type of asymmetric-membrane capsule,the capsule bodies were loaded with a powder mixture that contained 10wt % glipizide (a diabetes drug) and 90 wt % N-methylglucamine. Abouthalf the uncapped capsule body was submerged in simulated intestinalbuffer, with the open end of the capsule above the surface of thebuffer. Due to the osmotic driving force, water was imbibed into thecapsule bodies. The water imbibed into the capsule bodies was measuredby weight gain until the solution inside the capsule body filled thecapsule body and overflowed into the intestinal buffer.

Release-rate tests, such as those described in Examples 29, 30, 31, 36and 39, were conducted. The capsules were loaded with the same powdermixture as that used to load the capsule bodies for the water-fluxtests. About 70% of the glipizide was released from all of the capsulesat a constant rate. The steady-state release rate of glipizide (duringthe period of constant release) and the corresponding water flux isshown in FIG. 42 for each type of capsule. The release rates increase asthe water fluxes through the asymmetric-membrane capsule walls increase,as predicted by osmotic theory. Thus, by using the asymmetric-membranecapsules with the proper permeability to water, the desired release ratecan be achieved without changing the composition of the material loadedin the capsules.

EXAMPLE 48

Using standard techniques well known in the pharmaceutical industry, 3/8inch modified ball shape tablets were prepared to contain:

    ______________________________________                                        glipizide         20.0 mg                                                     N-methyl glucamine                                                                              246.2 mg                                                    microcrystalline cellulose                                                                      69.2 mg                                                     spray-dried lactose                                                                             69.2 mg                                                     hydroxypropyl cellulose                                                                          8.5 mg                                                     magnesium stearate                                                                              10.9 mg                                                     Total             424.0 mg                                                    ______________________________________                                    

The tablets were coated in a commercial perforated pan coating machine(Freund Hi-Coater model HCT 30) using a coating solution of thefollowing composition:

    ______________________________________                                        acetone           50.0 wt %                                                   ethanol           22.8 wt %                                                   n-butanol         12.4 wt %                                                   water              2.8 wt %                                                   glycerol           2.0 wt %                                                   cellulose acetate 398-10                                                                        10.0 wt %                                                   ______________________________________                                    

The coating process was stopped after the tablets had received a coatingequivalent to 42.4 mg cellulose acetate per tablet.

Upon examination with the scanning electron microscope, the tabletcoating was seen to consist of a largely porous layer which accountedfor most of the coating thickness, surmounted by a skin which wasperforated by numerous pores, but which was much less porous inappearance than the substructure. When placed in a standard USP-IIdissolution apparatus in USP simulated intestinal fluid, the tabletsreleased glipizide at a controlled rate, with 50% of the total dosedelivered in 3.5 hours and 90% delivered in 10-12 hours. When thetablets were dosed to fasted dogs, the plasma glipizide levels exhibiteda broad sustained delivery over ˜14 hours, attaining peak value in11±2.8 hours. The tablets were recovered from the feces and assayed forremaining drug. The drug remaining in the tablets was 10±2% of theoriginal dose. The bioavailability of the formulation relative to anoral sodium glipizide solution was 84%.

EXAMPLE 49

Non-pareil seeds (18-20 mesh) were placed in a 6 inch Wurster-typefluidized bed coating system (Lakso) and coated with a solution havingthe composition:

    ______________________________________                                        cellulose acetate 398-10                                                                          5%                                                        acetone            55%                                                        ethanol 95% USP    40%                                                        ______________________________________                                    

After the beads had received coating equivalent to 4.7 wt % celluloseacetate, the batch was discharged and passed through a 16 mesh sieve.The 4.7% coated beads were returned to the coating equipment andadditional coating was applied until the beads had received a total of9.71% coating. The batch was discharged and the partition in the coatingchamber was readjusted to obtain good fluidization. The batch wasreturned to the coating unit and coating resumed until the beads hadreceived a total of 25% coating. Upon examination by scanning electronmicroscopy, the coating on the beads was observed to consist of severalconcentric layers of asymmetric membranes. The total thickness of thecoating was ˜55 μm. The external surface of the coating appeared smoothand imperforate at a magnification of 4000×.

EXAMPLE 50

The following pseudoephedrine formulation was prepared as 1 mm beads bythe technique of extrusion/spheronization:

    ______________________________________                                        pseudoephedrine   50.0%                                                       N-methyl glucamine                                                                              20.0%                                                       lactose           15.0%                                                       microcrystalline cellulose                                                                      7.5%                                                        starch 1500       7.5%                                                        ______________________________________                                    

The drug-containing beads were coated in the Wurster coater as inExample 49. Samples of coated beads were withdrawn from the coatingequipment after they had received coatings of 15%, 30% and 45%. Uponmicroscopic examination, the coatings were found to consist ofconcentric layers (FIG. 43) of asymmetric membranes, as in the previousexample. The overall thickness of the coating was 40 μm for the 15%coating weight, 60 μm for the 30% coating, and 70 μm for the 45%coating. When tested in a USP dissolution tester in water at 37° C., the15% coated beads released 80% of their drug load in ˜2 hours, while the45% coated beads released 50% of their drug load in 4 hours and 80% oftheir drug load in 21 hours.

EXAMPLE 51

Capsules with asymmetric membranes were prepared by a semiautomatedrobotic process using a customized laboratory robot (Zymate II, Zymark,Hopkinton, Mass.). Six dip-fixtures each fitted with a stripping plateand fourteen aluminum moldpins were lubricated with silicone oil anddipped into a coating solution. The fixtures were withdrawn slowly over8 seconds, rotated twice in order to evenly distribute the coatingsolution over the entire surface, and then lowered into a quench bath.After 15 minutes in the quench bath, the coated mandrels were withdrawnand dried at room temperature for about 30 minutes. After the dryingstep, the capsule shells were stripped off the pins using the strippingplate, trimmed to size using a trimmer, and joined manually. Half of thefixtures had mold-pins corresponding to capsule bodies and the otherhalf had pins corresponding to capsule caps. The capsule dosage form wasassembled by filling the capsule body with a powder compositionconsisting of an active agent and other excipients, and sealing theinterface between the capsule body and cap (Quali-seal, Elanco, Ind.)using a sealing solution. The compositions of the coating, quench, andsealing solutions for capsules made from cellulose acetate (Form A) andfrom a mixture of ethylcellulose acetate and ethylcellulose (Form B) aregiven below in Table I.

The capsules were observed microscopically with a scanning electronmicroscope (SEM). The membrane was asymmetric with a relatively thin (6μm) dense skin formed on the surface of the capsule that was away fromthe mold pin and a thick (100 μm) porous substrate on the inner surfacewhich was in contact with the mold pin.

                  TABLE I                                                         ______________________________________                                        Composition of CA and EC/CA Capsules                                          Lubricant Polydimethyl Siloxane/Isopropyl Alcohol                             Methylene Chloride                                                                      Coating    Quench  Sealing                                          ______________________________________                                        FORM A (CA CAPSULES)                                                          Cellulose acetate                                                                         15.0                 15.0                                         Acetone     49.0                 56.9                                         Alcohol     28.0                 28.0                                         Glycerol    3.0          10.0                                                 Triethylcitrate                                                                           5.0                                                               Water                    90.0                                                 Dye                              0.1                                                      100.0        100.0   100.0                                        FORM B (EC/CA CAPSULES)                                                       Cellulose acetate                                                                         4.0                  15.0                                         Ethylcellulose                                                                            11.0                                                              Acetone     49.0                 56.9                                         Alcohol     28.0                 28.0                                         Glycerol    3.0          10.0                                                 Triethylcitrate                                                                           5.0                                                               Water                    90.0                                                 Dye                              0.1                                                      100.0        100.0   100.0                                        ______________________________________                                    

EXAMPLE 52

Capsules were made from cellulose acetate as in Example 51 but withdifferent ratios of glycerol/triethylcitrate. They were filled with amixture of glipizide, meglumine, and sodium bicarbonate, and sealedaccording to the procedure described in Example 51. The formulationdesignations for the fill composition and membrane combinations aregiven in Table II. The release profile of glipizide from theseformulations into 0.04 M TRIS are shown in FIG. 44.

                  TABLE II                                                        ______________________________________                                        MEMBRANE AND CORE FORMULATIONS - PLASTICIZER STUDY                            ______________________________________                                        A. MEMBRANE                                                                   Lubricant Polydimethyl Siloxane/Isopropyl Alcohol                             Methylene Chloride                                                            Designation →                                                                      TEC08        TEC53   TEC62                                        ______________________________________                                        Cellulose acetate                                                                         15.0         15.0    15.0                                         Acetone     49.0         49.0    49.0                                         Alcohol     28.0         28.0    28.0                                         Glycerol    8.0          3.0     2.0                                          Triethylcitrate                                                                           0.0          5.0     6.0                                                      100.0        100.0   100.0                                        ______________________________________                                        B. CORE                                                                                          a      b                                                   ______________________________________                                        Glipizide          12.0   12.0                                                Meglumine          70.0   50.0                                                Sodium Bicarbonate 17.5   37.5                                                Magnesium stearate 0.5    0.5                                                 ______________________________________                                        C. FORMULATION                                                                Designation      Membrane Core                                                ______________________________________                                        TEC08 - a        TEC08    a                                                   TEC08 - b        TEC08    b                                                   TEC53 - a        TEC53    a                                                   TEC53 - b        TEC53    b                                                   TEC62 - b        TEC62    b                                                   ______________________________________                                    

We claim:
 1. A device for the controlled release of one or more activesubstances into an environment of use, said device comprising a core ofsaid active substance or substances, with or without one or moreexcipients, surrounded by one or more asymmetric membranes, saidassymmetric membrane comprising a thick, porous region which supports adense, thin region.
 2. A device of claim 1, wherein the membrane ispermeable and imperforate and wherein the asymmetric membrane controlsthe release of the active substance or substances from the device.
 3. Adevice of claim 1, wherein the membrane is permeable and perforate andwherein the asymmetric membrane controls the release of the activesubstance or substances from the device.
 4. A device of claim 2, whereinthe release is substantially osmotic pumping.
 5. A device of claim 2,wherein the release is substantially diffusion.
 6. A device of claim 3,wherein the release is substantially osmotic pumping.
 7. A device ofclaim 3, wherein the release is substantially diffusion.
 8. A device ofclaim 1, wherein the asymmetric membrane is a cellulose ester or ethylcellulose.
 9. A device of claim 1, wherein said substance or substancesare biologically active.
 10. A device of claim 1, which is a tablet. 11.A device of claim 1, which is a capsule.
 12. A device of claim 1, whichis a bead.
 13. A device of claim 1, wherein the membrane issemipermeable and imperforate.
 14. A device of claim 13, wherein therelease is substantially osmotic pumping.
 15. A device of claim 14,which is a capsule, tablet or bead.
 16. A tablet, capsule or bead foradministration to an animal which releases one or more pharmaceuticallyactive substances into said animal which comprises a core of said activesubstance or substances, with or without one-or more pharmaceuticallyacceptable excipients, said core being surrounded by one or moreasymmetric membranes, said asymmetric membrane comprising a thick,porous region which supports a dense, thin region.
 17. A tablet, capsuleor bead of claim 16, wherein the administration is oral and the releaseis into the fluid of the gastrointestinal tract of said animal andwherein the asymmetric membrane controls the release of the activesubstance or substances from the device.
 18. A tablet, capsule or beadof claim 17, wherein the substance is an antihypertensive.
 19. A tablet,capsule or bead of claim 18, wherein the substance as prazosin.
 20. Atablet, capsule or bead of claim 18, wherein the substance isnifedipine.
 21. A tablet, capsule or bead of claim 18, wherein thesubstance as trimazosin.
 22. A tablet, capsule or bead of claim 18,wherein the substance as doxazosin.
 23. A tablet, capsule or bead ofclaim 17, wherein the substance as an antianxiety agent.
 24. A tablet,capsule or bead of claim 23, wherein the substance is hydroxyzine.
 25. Atablet, capsule or bead of claim 23, wherein the substance assertraline.
 26. A tablet, capsule or bead of claim 17, wherein thesubstance as an anticlotting agent.
 27. A tablet, capsule or bead ofclaim 26, wherein the substance is dazmegrel.
 28. A tablet, capsule orbead of claim 17, wherein the substance is a blood-glucose loweringagent.
 29. A tablet, capsule or bead of claim 28, wherein the substanceis glipizide.
 30. A tablet, capsule or bead of claim 17, wherein thesubstance is a decongestant, an antihistamine or cough or cold agent.31. A tablet, capsule or bead of claim 30, wherein the substance isbrompheniramine maleate.
 32. A tablet, capsule or bead of claim 30,wherein the substance is chlorpheniramine maleate.
 33. A tablet, capsuleor bead of claim 30, wherein the substance is phenylephrinehydrochloride.
 34. A tablet, capsule or bead of claim 30, wherein thesubstance is pseudoephedrine hydrochloride.
 35. A tablet, capsule orbead of claim 30, wherein the substance is cetirizine.
 36. A tablet,capsule or bead of claim 30, wherein the substance is dexbrompheniraminemaleate.
 37. A method for releasing one or more active substance orsubstances into an environment of use which comprises placing in saidenvironment a device containing said active substance or substancessurrounded by one or more asymmetric membranes, said asymmetric membranecomprising a thick, porous region which supports a dense, thin region.38. A method of claim 37, wherein the device is a tablet, capsule orbead.
 39. A method of claim 38, wherein the asymmetric membrane ispermeable and imperforate or perforate and wherein the asymmetricmembrane controls the release of the active substance or substances fromthe device.
 40. A method of claim 39, wherein the releasing issubstantially diffusion.
 41. A method of claim 39, wherein the releasingis substantially osmotic pumping.
 42. A method of claim 38, wherein theasymmetric membrane is semipermeable and imperforate.
 43. A method ofclaim 42, wherein the releasing is substantially osmotic pumping.
 44. Acapsule device for the controlled release of one or more activesubstances into an environment of use, said device comprising a core ofsaid active substance or substances, with or without excipients,enclosed in a capsule the top or bottom of which is comprised of one ormore asymmetric membranes, said asymmetric membrane comprising a thick,porous region which supports a dense, thin region.
 45. A device of claim44, wherein the membrane is permeable and perforate or imperforate andwherein the asymmetric membrane controls the release of the activesubstance or substances from the device.
 46. A device of claim 45,wherein the release is by osmotic pumping.
 47. A device of claim 6wherein the active substance is pseudoephedrine hydrochloride.
 48. Adevice of claim 47 wherein the asymmetric membrane comprises a celluloseacetate and a glycol.
 49. A device of claim 6 wherein the activesubstance is sertraline.
 50. A device of claim 49 wherein the asymmetricmembrane comprises a cellulose acetate and a glycol.